Copyright 2004 by the Genetics Society of America
Molecular and Comparative Genetics of Mental Retardation
Jennifer K. Inlow*,1 and Linda L. Restifo*,†,‡,2
*Arizona Research Laboratories Division of Neurobiology, †Department of Neurology, ‡Genetics GraduateInterdisciplinary Program, University of Arizona, Tucson, Arizona 85721-0077
Manuscript received August 14, 2003Accepted for publication November 14, 2003
ABSTRACTAffecting 1–3% of the population, mental retardation (MR) poses significant challenges for clinicians
and scientists. Understanding the biology of MR is complicated by the extraordinary heterogeneity ofgenetic MR disorders. Detailed analyses of �1000 Online Mendelian Inheritance in Man (OMIM) databaseentries and literature searches through September 2003 revealed 282 molecularly identified MR genes.We estimate that hundreds more MR genes remain to be identified. A novel test, in which we distributedunmapped MR disorders proportionately across the autosomes, failed to eliminate the well-knownX-chromosome overrepresentation of MR genes and candidate genes. This evidence argues against ascer-tainment bias as the main cause of the skewed distribution. On the basis of a synthesis of clinical andlaboratory data, we developed a biological functions classification scheme for MR genes. Metabolic path-ways, signaling pathways, and transcription are the most common functions, but numerous other aspectsof neuronal and glial biology are controlled by MR genes as well. Using protein sequence and domain-organization comparisons, we found a striking conservation of MR genes and genetic pathways across the�700 million years that separate Homo sapiens and Drosophila melanogaster. Eighty-seven percent have oneor more fruit fly homologs and 76% have at least one candidate functional ortholog. We propose thatD. melanogaster can be used in a systematic manner to study MR and possibly to develop bioassays fortherapeutic drug discovery. We selected 42 Drosophila orthologs as most likely to reveal molecular andcellular mechanisms of nervous system development or plasticity relevant to MR.
MENTAL RETARDATION (MR) is a common form clinical conditions affect such large numbers of childrenof cognitive impairment affecting between 1 and and young adults and yet have no effective pharmacolog-
3% of the population of industrialized countries (Roele- ical therapy. One reason for the lack of drug treatmentsveld et al. 1997; Aicardi 1998). Although there is de- is the limited understanding of the molecular and cellu-bate over the definition and classification of MR (Leo- lar bases for MR.nard and Wen 2002), it is often defined by an IQ of Many environmental and genetic factors can cause�70, with deficits in adaptive skills included as diagnos- MR, including premature birth, prenatal infections,tic criteria (Luckasson et al. 1992; Daily et al. 2000). chromosomal abnormalities, and single-gene mutationsBehavioral and cognitive therapies can help mentally (Kinsbourne and Graf 2000). An etiology can be estab-retarded patients reach their maximum potential (Bat- lished in 60–75% of cases of severe MR, but only inhaee 2001; Butler et al. 2001), but they are not curative 38–55% of mild cases. Estimates of genetic causes ofand often focus on treating habit disorders, aggression, severe MR range from 25 to 50% (McLaren and Bry-or self-injurious behavior that can accompany MR son 1987). There are two categories of hereditary MR.(Long and Miltenberger 1998; Dosen and Day 2001). Isolated MR with no other consistent defining featuresMR due to congenital hypothyroidism is now largely is known as nonspecific or nonsyndromal MR. To date,preventable through screening and hormone replace- all but one of these (Molinari et al. 2002) are X-linked,ment (Gruters et al. 2002). Aside from this, the only but other autosomal genes may have eluded identifica-molecular-based therapeutic approaches are dietary re- tion because of the considerably greater difficulty ofstrictions and supplements for inborn errors of metabo- mapping disorders to autosomal loci. MR also occurs,lism such as phenylketonuria (Dashman and Sansaricq with variable penetrance and expressivity, as a pheno-1993; Levy 1999; Kabra and Gulati 2003). Few, if any, typic feature of numerous hereditary syndromes. The
challenge of understanding the biological bases of he-reditary MR is heightened by its enormous genetic het-
1Present address: Department of Chemistry, Indiana State University, erogeneity and the limited knowledge of cellular pheno-Terre Haute, IN 47809. types in the brains of mentally retarded individuals.
2Corresponding author: Arizona Research Laboratories Division of Recent rapid progress in human genetics, however, hasNeurobiology, 611 Gould-Simpson Bldg., 1040 E. 4th St., University ofArizona, Tucson, AZ 85721-0077. E-mail: [email protected] provided us with an opportunity for a comprehensive
Genetics 166: 835–881 ( February 2004)
836 J. K. Inlow and L. L. Restifo
MATERIALS AND METHODSanalysis of the biochemical and cellular processes under-lying the MR phenotype. A search for “mental retarda- Databases and bioinformatics tools: The OMIM databasetion” in the Online Mendelian Inheritance in Man [McKusick-Nathans Institute for Genetic Medicine, Johns
Hopkins University and National Center for Biotechnology(OMIM) database (Hamosh et al. 2002) yields �1000Information (NCBI), National Library of Medicine; Hamoshentries, suggesting that hundreds of human genes canet al. 2002] was accessed online (http://www.ncbi.nlm.nih.mutate to a MR phenotype. We conducted a detailed gov/entrez/query.fcgi?db�OMIM) to search for genes and
analysis to determine how many MR genes have been mental retardation disorders. BLASTP (Altschul et al. 1997)molecularly identified and what molecular and biologi- at the NCBI (http://www.ncbi.nlm.nih.gov/BLAST/) and
the Homophila Human-Disease-to-Drosophila-Gene databasecal functions they encode.(Reiter et al. 2001; http://homophila.sdsc.edu/) were usedControversies over the definition of MR are based onto search for D. melanogaster homologs of the human MR genes.both sociopolitical and biological considerations (Leo- Pairwise sequence alignments were performed with LALIGN
nard and Wen 2002). Narrow definitions of MR restrict (http://www.ch.embnet.org/software/LALIGN_form.html;it to cases of nonprogressive cognitive impairment pres- Huang and Miller 1991). DotPlot and TransMem of the
Accelrys GCG Wisconsin Package were accessed through theent from birth and categorize as “dementia” cases ofArizona Research Laboratories Biotechnology Computing Fa-progressive cognitive deterioration beginning somecility and were used to compare homologous protein se-
time after a period of normal development. Nonethe- quences by dot matrix analysis (Maizel and Lenk 1981) andless, hereditary neurodegenerative disorders are often prediction of transmembrane regions, respectively. The In-
terPro resource for protein families, domains, and sitessaid to cause MR (see Stevenson et al. 2000), even(Apweiler et al. 2001; http://www.ebi.ac.uk/interpro/scan.when the onset is in late childhood or adolescence (e.g.,html) was used to determine and compare the locations ofprogressive epilepsy with mental retardation, one of thefunctional domains in homologous proteins. The Gene Ontol-
neuronal ceroid lipofuscinoses; CLN8). Moreover, the ogy (GO) database (Gene Ontology Consortium 2001) wasdistinction between MR and dementia blurs in disorders accessed online (http://www.geneontology.org/) to deter-
mine the molecular-function classification of MR gene prod-such as Rett syndrome (MECP2), where phenotypesucts. FlyBase (FlyBase Consortium 2002) was accessed on-span a wide spectrum of severity and clinical courseline (http://flybase.bio.indiana.edu/) to obtain information(Hammer et al. 2002). For the purpose of our analysison Drosophila genes. Newly isolated P-element insertions were
of hereditary MR, we chose a broader, albeit less precise, found through the P-Screen Database (http://flypush.imgen.definition that includes progressive disorders with onset bcm.tmc.edu/pscreen/).
Identifying human mental retardation genes throughof cognitive impairment in childhood and, occasionally,OMIM: We searched all OMIM fields on February 21, 2002,as late as adolescence.using the phrase “mental retardation” and reviewed each ofIn parallel with human genetics research, progress in the resulting 1010 entries. To include very mild MR, we also
Drosophila melanogaster genetics and genome sequencing searched for “cognitive impairment” and “learning disability,”(Adams et al. 2000) allows a comparative approach to obtaining 38 additional entries for evaluation. In retrospect,
“developmental delay” and “psychomotor retardation” wouldthe biological study of MR. Not only do homologoushave been useful search phrases as well. Other MR genes weremammalian and fruit fly genes share biological func-identified by periodic literature searches through Septembertions (Padgett et al. 1993; Bonini et al. 1997; Johnston 30, 2003, using NCBI’s PubMed.
et al. 1997; Leuzinger et al. 1998; Nagao et al. 1998; Careful evaluation of individual OMIM search results andDearborn et al. 2002), but also Drosophila provides cross-referencing with literature-search results revealed both
false positives and false negatives. OMIM contains many par-useful models of human disease, including spinocere-tially redundant entries, which makes it impossible to equatebellar ataxia (Warrick et al. 1998), Parkinson’s diseasenumbers of entries obtained from a search for a specific phe-(Feany and Bender 2000), Huntington’s disease (Jack- notype with the number of genes that can mutate to that
son et al. 1998), and type 1 diabetes (Rulifson et al. phenotype. OMIM entries for a genetic disorder or gene are2002). Moreover, neurodegeneration in the Drosophila organized into some or all of the following fields: title, MIM
number, gene map, clinical synopsis, text (literature sum-model of Huntington’s disease can be suppressed bymary), allelic variants, references, and contributors. Whentreatment with a specific peptide (Kazantsev et al.different mutations of a single gene cause distinct disorders,
2002). Hence, we propose that this neurogenetic model there are separate OMIM entries for each disease, but onlysystem can reveal cellular phenotypes responsible for one contains a list of disease-associated alleles (“allelic vari-
ants” field). For example, mutations in the L1CAM gene resulthereditary MR and will provide bioassays for potentialin one of at least three MR disorders (Weller and Gartnerdrug therapies. By searching the Drosophila genome,2001): MASA syndrome (mental retardation, aphasia, shuf-we found candidate functional orthologs for the major- fling gait, and adducted thumbs), HSAS (hydrocephalus due
ity of molecularly identified human MR genes. Several to congenital stenosis of the aqueduct of Sylvius), or SPG1dozen of these genes are most likely to have mutant (spastic paraplegia 1). There is a separate OMIM entry for
each of these disorders and a fourth entry for the L1CAMphenotypes due to primary developmental defects ofgene. There is some text redundancy among the four entries,neurons or glia and thereby provide clues to the causesbut only the L1CAM entry includes the allelic variants field.and treatment of MR due to single-gene mutations. On the basis of this organizational scheme, OMIM searches
Treatment strategies based on the understanding of restricted to entries containing the allelic variants field shouldeliminate redundant results. However, this strategy wouldhereditary MR may be useful for acquired MR as well.
837Molecular Genetics of Mental Retardation
cause false negatives because entries that list allelic variants Identifying Drosophila orthologs of human mental retarda-tion genes: We used bioinformatics tools to determine if thedo not necessarily contain complete phenotype descriptions.
For example, entry 600514, which lists the allelic variants of human MR genes have likely functional orthologs in D. melano-gaster. For MR genes encoding tRNAs, we aligned the humanreelin (RELN), does not contain the phrase “mental retarda-
tion,” whereas entry 257320 for Norman-Roberts type lis- and fly tRNA homologs using LALIGN and calculated thepercentage identity. For each protein-coding MR gene, wesencephaly syndrome due to RELN mutations contains the
search phrase but does not list allelic variants. In principle, searched the D. melanogaster sequences of the NCBI nonredun-dant database with NCBI’s BLASTP. We used an E -value cutoffthe “clinical synopsis” field could offer a useful search strategy
for disease phenotypes, but some are incomplete (e.g., the of 1 � 10�10 (1e -10), a threshold commonly used for human-clinical synopsis for Norman-Roberts lissencephaly does not fly gene comparisons (Fortini et al. 2000; Lloyd et al. 2000;include MR although it is a consistent phenotype of this disor- Reiter et al. 2001). The Homophila database (Reiter et al.der) and many entries have no clinical synopsis at all. 2001) is designed for such comparisons but, due to its organi-
Errors in the clinical synopsis fields also contributed to zational features and infrequent updates, we found it easierthe many (�15%) false-positive entries (see Table 1). For and more reliable to do our own BLAST searches. For oneexample, entries 167200 and 167210 for pachyonychia con- MR gene, we concluded that Drosophila does not have agenita types 1 and 2 include MR in their clinical synopses, biologically meaningful homolog despite a published claimbut the only evidence for MR is in the much rarer type 4 of one. Grunge (FBgn0010825) is the most similar fly gene(Feinstein et al. 1988). Other false positives result from state- to human DRPLA (Zhang et al. 2002), but has a BLASTPments such as “neither [patient] had evidence of mental retar- E -value of 5E-2, which does not meet our threshold. Moreover,dation” (entry 243605). In other entries MR is not a feature sequence similarity is limited to the extreme C terminus andof the disorder being described, but some atypical patients the Grunge protein does not possess the same domain organi-are mentally retarded due to deletion of adjacent genes (e.g., zation as DRPLA.entry 312865). Finally, MR may be mentioned because related For protein-coding MR genes, we also conducted a “reverse”disorders have a MR phenotype. For instance, MR is a pheno- BLASTP search using the top-scoring Drosophila BLASTP re-type of a subset of hereditary spastic paraplegias, so it is men- sult as a query against the human sequences of the NCBItioned in the text of the entries for most forms. Boyadjiev and nonredundant database. A Drosophila gene was consideredJabs (2000) noted similar difficulties in extracting information an ortholog of a human MR gene only if this reverse analysisfrom OMIM. To obtain complete information from OMIM, (sometimes supplemented with dot-matrix plot and protein-one must search in a manner that yields redundant and irrele- domain comparison; see below) revealed that it was morevant entries. This minimizes false negatives, but, to interpret similar to the human MR gene (or a paralog) than to anotherthe search results accurately, one must be willing to review gene. For example, the Drosophila proteins most similar toindividual entries carefully. Even using a broad OMIM search human glial fibrillary acidic protein (GFAP) are the productsstrategy, we missed 45 MR genes that were revealed through of Lamin and Lamin C. A reverse BLASTP search revealedvarious literature search strategies. that, although these two proteins share a single common do-
Functional classification of human mental retardation genes: main with GFAP, they are more similar over their full lengthsWe searched for the 282 MR gene products in the molecular- to members of the human lamin family. In addition, bothfunction category of the GO database and used information human and Drosophila lamins are localized to the nucleusfrom the literature to classify those not yet in the database. (Goldman et al. 2002), whereas GFAP is cytoplasmic (Eng et al.The GO database is composed of three parallel schemes for 2000). Hence, GFAP does not have an ortholog in Drosophila.classifying gene function: biological process, cellular compo- When compared with mammals, Drosophila has relativelynent, and molecular function (Gene Ontology Consortium few duplicated genes (Durand 2003), so in some cases a2001). Each ontology is a hierarchical classification scheme Drosophila gene is the single ortholog of a paralogous set of(directed acyclic graph) of structured vocabulary terms that human genes. For example, FMR1, which causes fragile Xdiffers from a simple hierarchical tree, such as a pedigree, in syndrome, is a member of a gene family that also includes FXR1that each term may be a “child” of multiple independent and FXR2, the autosomal fragile X-related genes. Drosophila“parents.” There are 24 occupied top-level terms in the molec- dfmr1 is the only homologous fly gene, sharing significantular-function ontology, i.e., terms that do not have parents sequence similarity and domain structure with all three humanthemselves. When GO assigned gene products to multiple genes, suggesting that it is the sole ortholog.molecular functions, we chose the most specific term for each. To determine if orthologous genes are likely to share theFor example, we classified the �-subunit of Gs, the adenyl- same molecular and biological functions in humans and flies,ate cyclase-stimulating guanine nucleotide-binding protein we used dot matrix plots (GCG DotPlot) to assess the extent(GNAS), as a “nucleotide-binding protein” rather than as a of protein sequence similarity and searched the InterPro data-“hydrolase,” the other GO assignment. For genes considered base for known functional domains in each protein. GCGby GO to have “unknown function,” we found that most could TransMem was used to predict transmembrane regions inbe provisionally classified on the basis of data in the literature. the human and fly proteins. If the proteins share sequenceThe “biological function(s)” assignments were based on similarity over most of their lengths and have similar organiza-literature reviews for each gene, including neuroimaging, tion of known functional domains, we considered them to begene expression, and neuropathological data from human candidate functional orthologs. In some cases we also consid-patients, as well as studies of wild-type and mutant mice. We ered expression patterns, mutant phenotypes, and subcellularfirst designated the basic cellular process in which the gene is localization. In cases of “computed genes” predicted from theprimarily involved, e.g., cytoskeleton or chromosome struc- Drosophila genome sequence, the absence of experimentalture. We then identified the site of primary organ system func- data made the evaluation of ortholog status more difficult.tion, relative to MR: endocrine system, central nervous system,or neither. For those genes that directly impact central nervoussystem (CNS) development and/or function, we ascertained
RESULTS AND DISCUSSIONthe tissue type (neuron, glia, or blood vessel) and the specificcellular process affected (e.g., cell identity or differentiation).
The 282 mental retardation genes have been molecu-We also considered whether MR caused by mutation of thegene is secondary to toxicity or secondary to energy or fuel deficiency. larly identified: Analysis of OMIM and literature search
838 J. K. Inlow and L. L. Restifo
TABLE 1
OMIM mental retardation entries
No. of % ofCategory Description entries entries
1 Known gene 254 25.12 Candidate gene 55 5.43 Chromosomal region 98 9.74 Candidate chromosome 26 2.65 Not mapped 416 41.26 Chromosomal abnormality 9 0.97 No MR phenotype 149 14.88 Nonexistent disorder 3 0.3
Total: 1010 100
This table is based on analysis of a search done on February21, 2002.
gene and allelic variants have been identified (thiscategory includes OMIM entries for the MR disordersas well as separate entries describing the genes them-Figure 1.—Diagram of the identification of human mentalselves).retardation genes and their comparison to D. melanogaster
Category 2: The disorder has been mapped to one orgenes. The OMIM searches were performed on February 21,2002. The literature search was completed on September 30, more candidate genes in a chromosomal region (con-2003. tiguous gene deletion syndromes, e.g., Prader-Willi,
are in this category).Category 3: The disorder has been mapped to a chromo-results allows us to present a status report on the genetics
somal region.of MR. From the 1010 OMIM “mental retardation” en-Category 4: The disorder has been mapped to a candi-tries obtained on February 21, 2002, we found 204 hu-
date chromosome.man genes that cause MR either in isolation or as partCategory 5: The disorder has not yet been mapped toof a syndrome. Through literature searches we found
a chromosome.45 additional MR genes whose OMIM entries did notCategory 6: The disorder is caused by a gross chromo-contain the search phrase “mental retardation.” About
somal abnormality and no single gene determines thea quarter of these “false-negative” entries contained theMR phenotype (Down syndrome is one example).phrases “psychomotor retardation” and/or “develop-
Category 7: MR is not a phenotype of the disorder.mental delay.” To include disorders causing very mildCategory 8: The disorder does not exist.MR, we also searched OMIM for entries containing “cog-
nitive impairment” or “learning disability” but not “men- The number of OMIM entries in category 1 (“knowntal retardation.” Most of these 38 entries describe adult- gene”), 254, is greater than the number of genes, 204,onset, progressive cognitive impairment disorders, but because of OMIM database redundancy (see materialsliterature review identified 4 of them as MR genes. Fi- and methods). The nearly 600 OMIM entries in catego-nally, literature searches between March 2002 and Sep- ries 2–5 represent MR disorders in which the causativetember 30, 2003 revealed 29 recently identified MR genes were unknown (see below). Of the 29 recentlygenes for a total of 282 human genes known to cause discovered MR genes, half had “advanced” from “candi-MR (Figure 1). On the basis of these and subsequent date gene” (1 gene), “chromosomal region” (9 genes),publications, we estimate that new MR genes are being or “unmapped” (5 genes) categories. Thirteen repre-identified at a rate of 1–2 per month. The appendix sent new loci that can cause a known disorder. Onelists the 282 MR genes in alphabetical order by their (FKRP) causes a form of muscular dystrophy, not pre-gene symbols, along with their associated MR disorders, viously associated with MR, that had been in category 7.chromosomal locations, OMIM numbers, and other in- Entries in category 6 (“chromosomal abnormality”)formation explained below. As will be discussed in later describe bona fide MR disorders, but we have not consid-sections, the MR genes control an extraordinary range ered them further in this analysis because they appearof molecular and cellular functions. to involve many genes (e.g., Shapiro 1999). It remains
We classified the 1010 OMIM “mental retardation” to be determined whether individual genes that contrib-entries, based on data available in spring 2002, ac- ute to MR in cases of aneuploidy or other chromosomalcording to the following scheme (Table 1):
defects can mutate to an MR phenotype individually.The 149 OMIM entries in category 7 (“no MR pheno-Category 1: The disorder has been mapped to a specific
839Molecular Genetics of Mental Retardation
type”) represent false positives in which MR is not a Fourth, mutations in genes controlling thyroid devel-opment or function rarely cause MR in industrializedphenotype (see materials and methods). Most ofsocieties because of neonatal screening and treatmentthese false-positive errors could be eliminated by thefor hypothyroidism (Gruters et al. 2002). Hence, whileadoption of a controlled vocabulary for OMIM clinicala dozen known genes have been associated with MRsynopses, with the previously mentioned caveat that MRsecondary to hypothyroidism (appendix), mutations indefinitions vary. The three entries in category 8 (“non-other similar genes may not have had the “opportunity”existent disorders”) do not represent distinct clinicalto reveal whether they would cause MR in untreatedentities, and one was subsequently removed from thepatients. Finally, syndromal MR genes for which the MROMIM database.phenotype has very low penetrance present a significantWith �600 OMIM MR entries in categories 2–5 (Ta-ascertainment challenge. For example, eight DNA re-ble 1), it is obvious that many more MR genes remain topair genes/disorders are associated with MR in a modestbe identified—but how many? Some of these disorders,fraction of patients. It seems likely that more such disor-particularly those in categories 4 (“candidate chromo-ders (e.g., the rarer Fanconi anemia complementationsome”) and 5 (“not mapped”), are likely to representgroups) have MR as a bona fide phenotype, but, presum-MR genes that are already known. This is because ofably because the phenotype depends on chance somaticboth practical difficulties in mapping human pheno-mutations during brain development (Gilmore et al.types and the phenomenon of phenotypic divergence;2000), it is difficult to confidently assign MR to theiri.e., different mutant alleles of the same gene causeclinical descriptions.distinct MR disorders (e.g., different DKC1 mutations
Given all these considerations, predicting the trueresult in dyskeratosis congenita or Hoyeraal-Hreidars-number of human MR genes is difficult. A complete andson syndrome). Similarly, novel MR genes that remainaccurate count may be beyond the capacity of medicalto be identified may each explain more than one disor-science to determine directly. We believe that 282 repre-der, especially within the large unmapped group.sents substantially less than half of the total. It is easyHence, this set of OMIM entries is likely to representto imagine that human MR genes could number �1000.�595 genes.
X-linked mental retardation genes: To date, eightOn the other hand, what MR disorders might beX-linked genes are known to cause exclusively nonspe-“missing” from our analysis? First, we know that somecific MR (MRX genes), and 31 X-linked genes causegenes, or their corresponding disorders, are present inexclusively syndromal forms of MR (Table 2). Nonspe-the OMIM database but fail to appear in MR-relatedcific MR has been the focus of much attention, in partsearch results because of inconsistent use of terminologybecause of the idea that genes with “pure” behavioral
in the medical literature, curatorial errors, or differingphenotypes, unaccompanied by gross brain abnormali-
opinions on what constitutes mental retardation (see ties or other organ system defects, may provide greatermaterials and methods). Second, MR mutations oc- insight into the molecular basis of cognition than thecurring in small families likely represent a large number syndromal MR genes (Chelly 1999; Toniolo 2000).of genes not yet listed in OMIM. Some families never Indeed, several MRX genes figure prominently in Rho-reach the attention of medical genetics research teams. type G-protein pathways (ARHGEF6, GDI1, OPHN1,Small pedigrees represent significant challenges for gene PAK3, FGD1; Ramakers 2002) or are regulated by neu-mapping, even on the X chromosome (Ropers et al. ronal activity (PAK3, IL1RAPL1, RSK2, TM4SF2; Boda2003). The X-Linked Mental Retardation Genes Update et al. 2002). However, with the discovery that mutationsSite (http://xlmr.interfree.it/home.htm; Chiurazzi et of five MR genes can cause either nonspecific or syndro-al. 2001) lists 57 nonspecific MR families and 110 mal MR (Table 2), the distinction between the two cate-X-linked MR syndromes for which the genes remain gories may not be as meaningful as originally proposedelusive. However, only 80 OMIM entries described (see discussion in Frints et al. 2002).X-linked MR disorders (syndromes and nonspecific) for For RSK2 (RPS6KA3), the phenotype difference iswhich genes have not been identified (Table 1, X-linked explained by allele type and severity. The R383W mu-entries in categories 2–4). tation that causes MRX19 is a partial loss-of-function
A third “missing” or underrecognized category is com- allele, encoding a protein with 20% of wild-type kinaseposed of essential genes of which most deleterious muta- activity (Merienne et al. 1999). In contrast, null mu-tions cause early prenatal lethality and only exceptional tations of RSK2 cause Coffin-Lowry syndrome withalleles with specific molecular consequences permit via- prominent skeletal and connective tissue involvementbility along with an MR phenotype. In genetic model (Hanauer and Young 2002). For several genes, thesystems, complementation testing can easily show that a structure-function relationships are inferred but not di-viable “memory mutation” is allelic to mutations causing rectly demonstrated. The T1621M mutation of ATRXearly death with profound neuroanatomical defects (also known as XH2 or XNP) causes nonspecific MR(e.g., Pinto et al. 1999), but comparable mapping stud- in the mild-to-moderate range (Yntema et al. 2002).
Although residue 1621 is within the highly conservedies are much more difficult in humans.
840 J. K. Inlow and L. L. Restifo
TABLE 2
X-linked mental retardation genes
Type of MR No. of XLMR % of XLMRdisorder genes genes Gene symbols (see also appendix)
Nonspecific only 8 18.2 ARHGEF6, FACL4, FMR2, GDI1, IL1RAPL1, OPHN1, PAK3, TM4SF2Syndromal only 31 70.5 All other X-linked genes in the appendixBoth 5 11.4 ARX, ATRX, FGD1, MECP2, RSK2Total 44 100
XLMR, X-linked mental retardation.
SNF2-related domain, it is not conserved, suggesting Chromosomal distribution of human mental retarda-tion genes: Of the 282 human MR genes, 11 are encodedthat some alterations at that site are compatible with
partial function of this nuclear protein involved in chro- by the mitochondrial genome. Figure 2A shows thechromosomal distribution of the 271 nuclear MR genesmatin structure and transcription regulation. Missense
mutations just 7 and 12 residues upstream, however, compared to the chromosomal distribution of all knownand predicted human genes based on the human ge-cause a more severe, syndromal phenotype with hemato-
logic, skeletal, and genital defects (Gibbons et al. 1995), nome sequence (Venter et al. 2001). While �4% ofknown and predicted genes are on the X chromosome,suggesting greater disruption of ATRX function. A vari-
ety of FGD1 mutations, most of which truncate the en- �16% of the MR genes reside there—a fourfold over-representation. In contrast, the distribution of MRcoded putative Rho GEF, cause Aarskog-Scott syndrome,
which includes highly penetrant skeletal and genital genes among the autosomes roughly parallels their rela-tive gene contents (Figure 2A). An even greater X-chro-anomalies but infrequent, and only mild, MR. In con-
trast, one particular missense mutation in a region of mosome overrepresentation is found among the MRdisorders mapped to candidate loci (6-fold), chromo-unknown function, P312L, causes severe, fully penetrant
nonspecific MR (Lebel et al. 2002). somal regions (14-fold), and chromosomes (15-fold),which correspond to categories 2, 3, and 4, respectively,Genotype-phenotype relationships are even more
complex for MECP2 and ARX. Within and among Rett of Table 1.It has been proposed that the human X chromosomesyndrome families, females with MECP2 mutations show
great clinical heterogeneity, with X-inactivation patterns contains a disproportionately high density of genes forcognitive ability (Lehrke 1972; Turner and Parting-and mutation sites believed to explain the severity differ-
ences (Cheadle et al. 2000; Hammer et al. 2002). In ton 1991). This proposal generated controversy as wellas speculation concerning possible underlying evolution-addition, at least seven different missense mutations in
MECP2, scattered over the length of the protein, cause ary mechanisms, including the intriguing suggestionthat female mate selection for high male intelligencenonspecific MR (Orrico et al. 2000; Couvert et al.
2001); several of these are very close to sites of Rett- helped accelerate the rapid rise of human cognitiveabilities (Turner 1996; Zechner et al. 2001). The identi-syndrome-causing missense mutations (Cheadle et al.
2000; Hammer et al. 2002). For ARX, identical muta- fication of numerous MRX genes and X-linked MR syn-dromes (Chiurazzi et al. 2001) seemed to support thetions, resulting in polyalanine tract expansion of this
homeodomain protein, caused nonspecific MR in one proposal. Opponents, however, argued that all X-linkedrecessive mutations are simply easier to map and identifyfamily, but distinct neurological syndromes (West or
Partington or MR with hypsarrhythmia) in various other because their phenotypes are revealed in hemizygousmales (Morton 1992; Lubs 1999). Countering this viewfamilies (Stromme et al. 2002). This suggests a major
effect of genetic background on ARX phenotypes. Other is an OMIM-based analysis (Zechner et al. 2001) show-ing a 7.2-fold X-chromosome bias for MR genes, whereasARX mutations cause a unique lissencephaly syndrome
with abnormal genitalia (Kitamura et al. 2002). genes causing common morphological phenotypes(polydactyly, cleft palate, facial dysplasia, skeletal dyspla-Complex genotype-phenotype relationships are also
a feature of some autosomal MR disorders (e.g., FGFR1, sia, and growth retardation) have, on average, only a2.4-fold X-chromosome bias. [Zechner et al. (2001) didGLI3, PEX1, PTEN, PTPN11). On the basis of X-linked
MR, it is possible that some alleles of the one known not take OMIM errors, such as false positives and nega-tives, into consideration, but such errors may be compa-autosomal nonspecific MR gene (PRSS12; Molinari et
al. 2002) will be found to cause a syndromal MR pheno- rable across phenotypes.]To take this question one step further, we askedtype. Conversely, autosomal genes presently known to
cause MR syndromes may be able to mutate to a nonspe- whether the apparent X-chromosome overrepresenta-tion among the molecularly identified human MR genescific MR phenotype.
841Molecular Genetics of Mental Retardation
(Figure 2A) would disappear if we accounted for theplausible possibility that numerous autosomal loci are“hiding” among the unmapped MR genes (representedby the OMIM entries in category 5, Table 1). We at-tempted to overcome the ascertainment bias that favorsidentification of X-linked genes by making simplifyingassumptions that maximize the estimate of autosomalMR genes and minimize the estimate of X-linked MRgenes. First, we assumed that one OMIM entry equalsone gene. Second, for the unmapped MR disorders(category 5, Table 1), we assumed that each representsa different, novel autosomal gene and that these aredistributed in proportion to the overall gene distribu-tion on those chromosomes (Venter et al. 2001). Third,for those disorders whose genes map to chromosomalregions and candidate chromosomes (categories 3 and4, Table 1), we assumed that there will be no newX-linked genes, i.e., that each potential X-linked geneis identical to an X-linked gene already known to causeMR. However, all candidate genes (category 2, Table1), including the X-linked genes, were assumed to benew MR genes.
Even when these very conservative (i.e., biased towardautosomal) assumptions are used to estimate the chro-mosomal distribution of the unknown MR genes, a 1.9-fold overrepresentation of MR genes on the X chromo-some remains (Figure 2B). This result supports thehypothesis that the X chromosome contains a dispro-portionately high density of genes influencing cognitiveability. One caveat is the possibility discussed above thatmany autosomal MR genes may be so rare or difficultto study that they never appear in the medical literatureand, hence, in OMIM. We also agree with the suggestionof Lubs (1999) that resolution of this issue would beenhanced by analyzing genome-wide brain expressiondata and by searching for allelic variation in single genesresponsible for the high end of the intelligence spec-trum.
D. melanogaster homologs of human mental retarda-tion genes: We found that 87% of known MR genes(246/282) have at least one Drosophila homolog witha BLASTP E-value of 1 � 10�10 or better (Figure 1;Figure 2.—Chromosomal distribution of human mentalappendix). Similarly, Reiter et al. (2001) found thatretardation genes and D. melanogaster orthologs. (A) The chro-
mosomal distribution of the 271 molecularly identified nu- 75% of �1400 human disease genes, representing allclear MR genes is compared to the chromosomal distribution major disease categories, have Drosophila homologs atof all nuclear, protein-coding human genes based on human this level of sequence similarity. More important, 76%genome sequence analysis (Venter et al. 2001). Note the
(213) of the MR genes, including syndromal and non-striking overrepresentation of X-linked MR genes. (B) Thesyndromal types, have at least one Drosophila orthologpredicted chromosomal distribution of known and potential
MR genes based on maximizing the assignment of genes to (see materials and methods and appendix). In fact,autosomes (see results and discussion), compared to all a handful of the human genes were named for theirnuclear human genes as in A. The X-chromosome overrepre- Drosophila orthologs, in most cases prior to their identi-sentation has been reduced, but remains almost twofold. (C)
fication as MR genes (ASPM : abnormal spindle-like, micro-The chromosomal distribution of the Drosophila MR genecephaly-associated ; EMX2 : homolog 2 of empty spiracles ;orthologs is compared to the chromosomal distribution of
all nuclear, protein-coding Drosophila genes on the basis of PTCH : homolog of patched ; PTCH2 : homolog 2 of patched ;Drosophila genome sequence analysis (Adams et al. 2000; see SHH : sonic hedgehog ; SIX3: homolog 3 of sine oculis).FlyBase at http://flybase.bio.indiana.edu/ for Release 3). Dro- The appendix lists the Drosophila homologs and or-sophila homologs of human MR genes that are not orthologs
thologs of the MR genes, their FlyBase accession num-were not included in this analysis.
842 J. K. Inlow and L. L. Restifo
bers, and the BLASTP E-values (see also Figure 1 for the GO database (Figure 3; appendix; see materialsand methods). The MR genes are distributed over aoverview). As discussed below, several dozen Drosophilabroad range of functions, indicating that disruption oforthologs (designated “¶” in the appendix) are primeany of a wide array of molecular processes can impaircandidates for cellular and molecular study of MR. Sev-brain function so as to cause MR. Several categories areenteen MR genes (6%; designated with asterisk) haveprominently represented, such as enzymes (143 genes;one or more homolog(s) that may be orthologs, but it51%), mediators of signal transduction (32 genes; 12%)is not possible to make a determination on the basis ofand transcription regulation (19 genes; 7%), bindingsequence analysis in the absence of experimental data.proteins (23 genes; 8%), and transporters (21 genes;Another 16 MR genes (6%; in brackets) have one or8%). Enzymes, especially those expressed in accessiblemore Drosophila homolog(s) that are not orthologs onperipheral tissues, make gene identification easier thanthe basis of reverse BLAST results or other sequencethat for many other proteins, so their relative represen-analysis (see materials and methods). There are 36tation may decline as new MR genes are discovered.MR genes (13%) with no Drosophila homolog, al-Other categories with smaller numbers of MR genesthough this number may decline as final gene identifi-include cell adhesion molecule, structural molecule,cation for the Drosophila genome is completed.motor protein, tRNAs, apoptosis regulator, chaperone,Some of the Drosophila genes are functional or-and enzyme regulator. GO classifies �9% of the MRthologs of human MR genes on the basis of experimen-genes (25) in the “unknown function” category, buttal data. For instance, mutations of dfmr1, the Drosoph-published data suggest functions for all but 10 of themila ortholog of fragile X mental retardation 1 (FMR1; Wan(see appendix).et al. 2000), cause specific disruptions of neuronal mor-
Within the GO molecular-function ontology, top-levelphology (Zhang et al. 2001; Morales et al. 2002; Leecategories include fundamental molecular functionset al. 2003; C. Michel, R. Kraft, B. Hassan and L.(e.g., binding activity, of which there are many subcate-Restifo, unpublished results) and behavioral defectsgories), as well as others related to a specific cellular(Dockendorff et al. 2002; Inoue et al. 2002). Geneticprocess (e.g., cell adhesion molecule), and in manyand biochemical data suggest that Drosophila dFMR1cases, genes could be assigned to more than one. Thisis a regulator of translation (Zhang et al. 2001; Ishizukamakes classification, analysis, and comparison to otheret al. 2002), as has been shown for mammalian FMRPsets of genes somewhat difficult. We did not classify any(Kaytor and Orr 2001; Laggerbauer et al. 2001; Maz-MR gene products as “defense/immunity proteins,” butroui et al. 2002; Zalfa et al. 2003). Although learningIKBKG encodes a subunit of a signal transducer (ourphenotypes of dfmr1 mutant flies have not yet beencategory choice) that regulates NF-�B in the immune
reported, four of the fruit fly MR gene orthologs areand inflammatory response pathway (Wallach et al.
“learning and memory genes” on the basis of behavioral 2002). We also did not use the “translation regulator”data: G protein s�60A (Connolly et al. 1996), the or- category, but EIF2AK3 encodes a kinase (our categorytholog of GNAS; Neurofibromin 1 (Guo et al. 2000), the choice) that indirectly regulates translation by phos-ortholog of NF1; cheerio (see Dubnau et al. 2003, online phorylating eukaryotic translation initiation factor-2supplement), the ortholog of FLNA; and S6kII or igno- (Ma et al. 2002). Similarly, we classified FMR1 as “RNArant (G. Putz, T. Zars, and M. Heisenberg, personal binding,” but considerable data demonstrate that it reg-communication), the ortholog of RSK2. Additional Dro- ulates translation (Jin and Warren 2003). In addition,sophila learning and memory genes have been pro- we could have classified some genes in the “proteinposed as candidates for MR disorders that are not yet stabilization” (e.g., PPGB), cytoskeletal regulator (e.g.,mapped (Morley and Montgomery 2001). TBCE), or “protein tagging” (e.g., UBE3A) categories.
The Drosophila orthologs of the human MR genes However, anticoagulant, antifreeze, antioxidant, chap-do not have a skewed chromosomal distribution (Figure erone regulator, nutrient reservoir, and toxin are top-2C). Approximately 16% of all fly genes and 16% of level categories in which none of the 282 MR genesMR gene orthologs are on the X chromosome. Of the could be placed.first two dozen Drosophila “learning and memory Figure 3 indicates the Drosophila-homolog status ofgenes” identified, almost 50% are X-linked (reviewed in the MR genes in each molecular-function category. TheDubnau and Tully 1998; Morley and Montgomery 213 MR genes with Drosophila ortholog(s) (solid bars)2001). However, the recent isolation of 60 new auto- are distributed among the GO categories in roughlysomal memory genes (Dubnau et al. 2003) indicates the same pattern as that of all the MR genes, with twothat the older results reflect the previous tendency to exceptions. More than half of the “receptor binding”design X-chromosome screens for behavioral and genes (4 of 7) and 36% (9 of 25) of the “unknownneuroanatomical phenotypes. function” MR genes have no Drosophila homolog.
Molecular functions of mental retardation genes: Biological functions of mental retardation genes: WeEach of the 282 MR genes was classified in a single devised a “biological function(s)” classification scheme
for the 282 MR genes that considers both cellular- andmolecular-function category, primarily on the basis of
843Molecular Genetics of Mental Retardation
Figure 3.—Molecular function classification ofmental retardation genes. Genes were classifiedon the basis of GO categories (see materials andmethods). In cases where the top-level parentterms include large numbers of genes (signaltransduction, binding, transcription regulation,enzyme), we show the distribution of genesamong the children terms. For many of the genesthat have not yet been classified by the GO Con-sortium, we used information from the literatureto assign them to a GO term. For some of thegenes designated “unknown function” by GO, wewere able to assign provisional functions on thebasis of published literature (see appendix), butthese genes are included in the “unknown func-tion” category of this figure. As indicated by theboxed legend, each bar indicates classification ofthe human MR genes based on the degree ofsimilarity to Drosophila genes.
systems-level perspectives (Figure 4; appendix; see ma- The major signaling pathways are represented amongthe MR genes, including those regulated by Sonicterials and methods). The basic cellular processes con-
trolled by MR genes take place in the nucleus, in the Hedgehog (e.g., SHH), the TGF-� family of growth fac-tors (e.g., GPC3), Notch (e.g., JAG1), and calcium (e.g.,cytoplasm (including within organelles), and at the in-
terface among cells, cell compartments, and the extra- ATP2A2). MR-related signaling cascades are mediatedby diverse cell surface proteins, such as integrins (e.g.,cellular milieu. In the nucleus, MR genes affect chromo-
some structure (e.g., DNMT3B), DNA repair (e.g., NBS1), ITGA7), G protein-coupled receptors (e.g., AGTR2), re-ceptor tyrosine kinases (e.g., NTRK1), and intracellularbasal and regulated transcription (e.g., ERCC2 and SIX3,
respectively), as well as rRNA processing (e.g., DKC1). proteins, including small G proteins (e.g., GDI1), hetero-trimeric G proteins (e.g., GNAS), and phosphatidylinosi-In the cytoplasm, many MR genes have metabolic
functions (see also Kahler and Fahey 2003), involving tol (e.g., PTEN). Moreover, genes in a common pathwaycan share MR as a phenotype. SHH (Ming et al. 1998),a wide range of pathways [citric acid cycle (e.g., FH),
gluconeogenesis (e.g., GK), glycolysis (e.g., PDHA1), oxi- through its receptors encoded by PTCH and PTCH2,regulates GLI3, some of whose targets are also regulateddation (e.g., the PEX genes), oxidative phosphorylation
(e.g., MTCO1), urea cycle (e.g., OTC), and general cell by GPC3.MR genes also control communication and transportintegrity (e.g., GSS)] and biologically critical com-
pounds [amine (e.g., MAOA), amino acid (e.g., OAT), across cell and organelle membranes. These includecation-chloride cotransporters (SLC12A1, SLC12A6)carbohydrate (e.g., GALE), cholesterol (e.g., SC5DL),
creatine (e.g., GATM), fatty acid (e.g., ALDH3A2), heme that may be critical for inhibitory neurotransmission(Payne et al. 2003). The transmembrane linkage (ITGA7,(e.g., PPOX), lipid (e.g., DIA), methionine (e.g.,
MAT1A), purine (e.g., HPRT), pyrimidine (e.g., DPYD), TM4SF2) between the extracellular matrix (LAMA2) andthe cytoskeleton is strongly implicated in MR, as is celland cofactors (e.g., TC2)]. MR genes involved in macro-
molecular synthesis and modification include those re- adhesion (L1CAM).The overlap between MR and muscle disease is strik-quired for mitochondrial translation (e.g., MTTK),
translation regulation (e.g., FMR1), protein folding (e.g., ing and appears to arise from at least three distinctmechanisms: reduced membrane/cytoskeletal stabilityBBS6), protein stability (e.g., PPGB), protein glycosyla-
tion (e.g., PPM2), and lipid synthesis (FACL4). Macro- (DMD, ITGA7, LAMA2); glycosylation defects associatedwith abnormal neuronal migration (FCMD, FKRP,molecular degradation in lysosomal (e.g., HEXA) and
proteasomal (e.g., UBE3A) pathways is also commonly LARGE, POMGNT1, POMT1); and mitochondrial dys-function (MTCO3 and many others). The biologicaldisrupted by mutations in MR genes. MR genes have
major effects on the cytoskeleton, including its actin basis of myotonic dystrophy (DM1) is unknown.An integrative view of MR biology: The hereditary(e.g., FLNA), microtubule (e.g., DCX), and intermediate
filament (e.g., GFAP) components. MR disorders can be approached from two somewhat
844 J. K. Inlow and L. L. Restifo
Figure 4.—Biological functions that underliemental retardation. Diagram of a mammalian cor-tical neuron and associated structures in the cen-tral nervous system. The physiological connectionto the endocrine system via the bloodstream isindicated in the bottom left. Sizes are not to scale.Solid triangles represent hormone molecules.Each of the unboxed terms, in roman type, is abiological function regulated by one or more MRgenes or results from mutation of an MR gene(see appendix).
independent perspectives: (i) where the genes are ex- pancreas to regulate ATP-dependent, exocytotic insulinsecretion. Mutations in either gene cause excess insu-pressed and function and (ii) the relationship between
the mutation and pathogenesis of the MR phenotype. lin release and hypoglycemia which, if inadequatelytreated, disrupts brain development and function dueGenes may act selectively within the brain (“intrinsic
or selective function”) or primarily outside the CNS to systemic fuel deficiency (Vannucci and Vannucci2001; Huopio et al. 2002). Similarly, the brain’s energy(“extrinsic or generalized function”). MR may result
from fundamental cellular defects that impair many requirements make it very sensitive to genetic disrup-tions of mitochondrial function (Chow and Thorburntissues (“generic effect”), with the brain sometimes hav-
ing a higher sensitivity, or MR can result from selective 2000). Mutations in mitochondrial genes (MTATP6,MTCO1, MTCO2, MTCO3, MTCYB, MTTE, MTTK,impairment of unique features of brain development
or physiology (“selective effect”). With the caveat that MTTL1, MTTS1) or in nuclear genes encoding mito-chondrial proteins (BCS1L, SCO2, SURF1, TIMM8A)MR pathogenesis is incompletely understood and that
spatial expression data are limited, we consider exam- cause MR due to local energy (ATP) deficiency in neu-rons and glia (Servidei 2001).ples of MR genes in these major categories.
Extrinsic or generalized function/generic effect: ABCC8 Extrinsic or generalized function/selective effect: In the en-docrine system, locally synthesized hormones enter the(SUR1) and KCNJ11 gene products work together in the
845Molecular Genetics of Mental Retardation
circulation and affect distant organs. MR genes include aly (“smooth brain”) due to mutations in LIS1, DCX,and RELN, as well as ARX (some alleles) and FLNAseveral tissue-specific regulators of thyroid gland devel-
opment (TTF2, PAX8) or thyroid hormone synthesis (Olson and Walsh 2002). Agenesis (partial or com-plete) and dysgenesis of the interhemispheric corpus(DUOX2, TG, TPO ; Kopp 2002). Mutations in these
cause congenital hypothyroidism, and mutations in a callosum (Davila-Gutierrez 2002) are relatively com-mon MR-associated phenotypes (e.g., CXORF5, GLI3,receptor (THRB) cause thyroid hormone resistance. In
either case, brain cells cannot initiate the transcriptional OCRL, SLC12A6, TSC1, TSC2) and may be isolated oraccompany holoprosencephaly and other abnormali-cascade that controls neuronal size, migration, and den-
dritic morphology, as well as oligodendrocyte differenti- ties.A handful of MR genes and their primary cellularation (Thompson and Potter 2000). Hence, neuronal
circuitry and myelination are disrupted. phenotypes are glia specific. Dominant missense muta-tions in GFAP cause Alexander disease due to astrocyticMany metabolic MR genes fall into this category as
well. AASS is expressed in most tissues and encodes a accumulation of abnormal intermediate filaments andsecondary demyelination (Johnson 2002). In contrast,key enzyme in lysine metabolism (Sacksteder et al.
2000). In patients lacking AASS function, lysine accumu- PLP1 is expressed solely in oligodendrocytes and en-codes the most abundant CNS myelin protein. Myelinlates and inhibits arginase, causing excess circulating
ammonia, which interferes with neuronal and glial func- integrity is very sensitive to PLP1 gene dosage, with du-plications, deletions, and missense mutations all caus-tions (Felipo and Butterworth 2002). Similarly, PAH
is expressed mainly in nonneural tissues (Lichter- ing Pelizaeus-Merzbacher disease (Koeppen and Robi-taille 2002).Konecki et al. 1999), with mutations causing elevated
circulating phenylalanine. This systemic toxin impairs At the other end of the spectrum are the many heredi-tary MR disorders for which routine neuropathologicalmyelination, synaptogenesis (Bauman and Kemper
1982; Huttenlocher 2000), and possibly aminergic data are unavailable or fail to show consistent defects.Higher-resolution Golgi staining has revealed dendriticneurotransmission (Surtees and Blau 2000). The lyso-
somal storage disorders, which cause macromolecules abnormalities of cortical neurons in fragile-X (FMR1;Irwin et al. 2000) and Rett syndromes (MECP2; Arm-to accumulate in many tissues, may also belong to this
category. Most represent degradative enzyme deficien- strong 2001) and possibly in Rubinstein-Taybi syn-drome (CREBBP ; Kaufmann and Moser 2000). Allcies, but some of the genes encode transport, stabilizer,
or activator proteins (Wisniewski et al. 2001). They are three likely result from misregulated gene expressionin the brain, but which target genes are responsible forclassified by the compounds that accumulate in lyso-
somes, such as sphingolipidoses (e.g., ARSA), neuronal the dendritic defects remain to be determined.For MR disorders with no known anatomical lesions,ceroid lipofuscinoses (e.g., CLN1), glyoproteinoses (e.g.,
PPGB), and mucolipidoses (e.g., NEU1). The traditional such as nonsyndromal MRX, gene function in the CNSis inferred from molecular analyses. For example, GDI1view that the progressive brain phenotypes result “sim-
ply” from local toxicity is countered by reports of specific (MRX41, MRX48; Bienvenu et al. 1998) encodes abrain-specific regulator of Rab-type G proteins. One ofneurodevelopmental defects (Walkley 1998; Alta-
rescu et al. 2002). its targets is believed to be Rab3A, which controls activ-ity-dependent synaptic vesicle recruitment to axon ter-Intrinsic function/selective effect: For genes with selective
expression or function within the CNS, the conse- minals (Leenders et al. 2001). Given the structure-func-tion relationships underlying developmental synapticquences of mutations are also primarily CNS selective,
with variation in cell-type involvement and severity plasticity (Cohen-Cory 2002), it seems likely that neuro-anatomical phenotypes for this and other MRX disor-(Pomeroy and Kim 2000). The coexistence of neuro-
pathology and cognitive deficits supports the view of ders will eventually be found.Regardless of the scheme used, many disorders defyMR as a disorder of brain development or plasticity. At
one end of the spectrum are MR disorders with gross straightforward classification. For example, the role ofhomocysteine in CNS development and functionbrain malformations. Holoprosencephaly, a failure of
the right and left brain halves to form distinct hemi- (Mattson and Shea 2003) belies the “metabolic” classi-fication of the MR genes CBS, MTHFR, MTR, MTRR,spheres, results from mutations in genes controlling
cellular identity of forebrain neuronal precursors and TC2. The MR genes SC5DL and DHCR7 encodeenzymes in cholesterol biosynthesis, making them also(PTCH, SHH, SIX3, TDGF1, TGIF, ZIC2; Wallis and
Muenke 2000). Schizencephaly (“cleft brain”) is due to primarily “metabolic.” However, because Sonic Hedge-hog protein function is absolutely dependent on cova-dominant missense mutations in EMX2, which encodes
a homeodomain-containing transcription factor (Faiella lent linkage to cholesterol (Ingham and McMahon2001), the enzymatic deficiencies may impair SHH sig-et al. 1997). Abnormal neuronal migration in the rostral
forebrain (the region of EMX2 expression) causes gross naling. It may be that, with sufficient research on molec-ular and cellular pathogenesis, few if any MR genes willmorphogenetic as well as more subtle lamination de-
fects. Neuronal migration defects also cause lissenceph- be considered “just metabolic.”
846 J. K. Inlow and L. L. Restifo
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cofa
ctor
Cer
ebra
lat
roph
y;↓G
lyR
and
Yes/
yes
cinn
amon
1AYe
sM
olyb
den
umco
fact
orbi
osyn
thes
isde
fici
ency
type
CG
AB
A-R
clus
teri
ng
GPI
(18)
Hem
olyt
ican
emia
?Los
sof
neu
rotr
oph
icac
tivi
tyYe
s/?
pgi
44F
Yes
Glu
cose
met
abol
ism
;[n
euro
nal
surv
ival
]IT
GA
7(1
9)C
onge
nit
alm
yopa
thy
Cor
tica
lat
roph
y;ab
nor
mal
Non
em
ew11
EYe
s,N
Tis
sue
adh
esio
n;c
ellm
igra
tion
;axo
nw
hit
em
atte
rpa
thfi
ndi
ng
(con
tinue
d)
847Molecular Genetics of Mental Retardation
TA
BL
E3
(Con
tinu
ed)
Dro
soph
ilaor
thol
og
Mam
mal
ian
brai
nM
ouse
Gen
eH
uman
gen
eaH
uman
dise
aseb
phen
otyp
ein
clud
es:c
mut
ant/
MR
dG
ene
nam
eelo
cati
onM
utan
tsB
iolo
gica
lfu
nct
ion
inD
roso
phila
f
JAG
1(2
0)A
lagi
llesy
ndr
ome
Abn
orm
alve
ssel
s(m
oyam
oya)
Yes/
?Se
rrat
e97
EYe
s,N
Not
chpa
thw
ay;
cell
fate
;an
dn
euro
nal
patt
ern
ing
neu
roge
nes
isL
1CA
M(2
1)M
ASA
syn
drom
e;H
SAS;
AC
C;
hyd
roce
phal
usYe
s/ye
sne
urog
lian
7FYe
s,N
Neu
ron
adh
esio
n/m
orph
olog
y;ax
onSP
G1
path
fin
din
gL
AM
A2
(22)
Con
gen
ital
mus
cula
rA
bnor
mal
lam
inat
ion
and
Yes/
yes
win
gbl
iste
r35
AYe
sC
ell
mig
rati
onan
dad
hes
ion
dyst
roph
yw
hit
em
atte
r;↓c
ereb
ellu
mL
IS1
(23)
Lis
sen
ceph
aly;
↓Cor
tica
lla
min
atio
n:
Yes/
yes
Lis
senc
epha
ly-1
52F
Yes,
NN
euro
gen
esis
;de
ndr
itog
enes
is;
peri
ven
tric
ular
pach
y/ag
yria
,h
eter
otop
iaax
onal
tran
spor
th
eter
otop
iaM
ID1
(24)
Opi
tzsy
ndr
ome
type
IA
CC
and
oth
erm
idlin
eN
one
CG
3172
132
AN
P?E
mbr
yon
icC
NS
deve
lopm
ent
defe
cts;
cort
ical
atro
phy
(CG
6256
)M
YO5A
(25)
Ele
jald
esy
ndr
ome
Cer
ebel
lar
hyp
opla
sia;
Yes/
yes
didu
m43
DU
PE
mbr
yoge
nes
isab
nor
mal
den
drit
icsp
ines
NF1
(26)
Neu
rofi
brom
atos
isM
egen
ceph
aly;
abn
orm
alYe
s/ye
sN
euro
fibro
min
196
FYe
s,N
Ras
path
way
;gl
ial
grow
th;
lear
nin
g/w
hit
em
atte
r;gl
ial
tum
ors
mem
ory
NSD
1(2
7)N
ijmeg
enbr
eaka
geA
CC
;po
lygy
ria;
dila
ted
Non
eM
es-4
98B
NP
[Tra
nsc
ript
ion
regu
lati
on]
syn
drom
eve
ntr
icle
sO
CR
L(2
8)L
owe
ocul
ocer
ebro
ren
alA
CC
;ab
nor
mal
wh
ite
mat
ter
Yes/
no
EG:8
6E4.
52B
NP
[In
osit
olph
osph
ate
path
way
;sy
ndr
ome
?pro
tein
sort
ing]
OPH
N1
(29)
MR
X60
Pres
umed
toh
ave
no
obvi
ous
Non
eG
raf
13E
NP;
R;
NA
xon
stab
ility
defe
cts
PAK
3(3
0)M
RX
30;
MR
X47
No
obvi
ous
defe
cts
Non
ePa
k83
EYe
s,N
Axo
npa
thfi
ndi
ng
PRSS
12(3
1)A
utos
omal
rece
ssiv
ePr
esum
edto
hav
en
oob
viou
sN
one
Teq
uila
66F
NP
[Ser
ine
prot
ease
]n
onsp
ecifi
cM
Rde
fect
sPT
EN(3
2)C
owde
nsy
ndr
ome;
Meg
ence
phal
y;ab
nor
mal
Yes/
yes
Pten
31B
Yes
Cel
lsi
zean
dpr
olif
erat
ion
;in
sulin
Ban
nay
an-Z
onan
ala
min
atio
n;↑n
euro
nsi
zepa
thw
aysy
ndr
ome
PTPN
11(3
3)N
oon
ansy
ndr
ome;
Un
know
nYe
s/?
cork
scre
w2D
Yes,
NR
TK
path
way
s;ce
llfa
te,
mig
rati
on,
LE
OPA
RD
syn
drom
epa
thfi
ndi
ng
RSK
2(3
4)C
offi
n-L
owry
syn
drom
e;A
CC
;di
late
dve
ntr
icle
sYe
s/ye
sS6
kII
20A
Yes,
N[S
ign
alin
gpa
thw
ays]
;le
arn
ing
and
MR
X19
mem
ory
SHH
(35)
Hol
opro
sen
ceph
aly
3H
olop
rose
nce
phal
y;ve
ntr
alYe
s/ye
she
dgeh
og94
EYe
s,N
Mor
phog
enex
pres
sion
;pa
tter
nin
g;fa
tefa
ilure
neu
roge
nes
isSI
X3
(36)
Hol
opro
sen
ceph
aly
2H
olop
rose
nce
phal
yN
one
Opt
ix44
AN
PIn
duce
sey
ede
velo
pmen
tSO
X3
(37)
MR
wit
hgr
owth
hor
mon
eU
nkn
own
Non
eSo
xNeu
ro29
FYe
s,N
Cel
lfa
te;
neu
roge
nes
is;
axon
defi
cien
cygu
idan
ceT
BC
E(3
8)H
RD
syn
drom
eU
nkn
own
;?ax
onde
gen
erat
ion
Yes/
yes
CG
7861
42A
UP
[Ch
aper
one;
tubu
linfo
ldin
gan
d(s
eeap
pen
dix
)di
mer
izat
ion
]
(con
tinue
d)
848 J. K. Inlow and L. L. Restifo
TA
BL
E3
(Con
tinu
ed)
Dro
soph
ilaor
thol
og
Mam
mal
ian
brai
nM
ouse
Gen
eH
uman
gen
eaH
uman
dise
aseb
phen
otyp
ein
clud
es:c
mut
ant/
MR
dG
ene
nam
eelo
cati
onM
utan
tsB
iolo
gica
lfu
nct
ion
inD
roso
phila
f
TSC
2(3
9)T
uber
ous
scle
rosi
s2
Cor
tica
ltu
bers
;su
bcor
tica
lYe
s/ye
sgi
gas
76F
Yes,
NC
ells
ize;
cell
cycl
e;ax
onpa
thfi
ndi
ng
nod
ules
;as
troc
ytom
asU
BE3
A(4
0)A
nge
lman
syn
drom
e“A
trop
hy”
;ab
nor
mal
gyra
lYe
s/ye
sC
G61
9068
BU
P[S
elec
tive
prot
ein
degr
adat
ion
]pa
tter
n;↓d
endr
itic
arbo
rsZI
C2
(41)
Hol
opro
sen
ceph
aly
5H
olop
rose
nce
phal
y;de
fect
ive
Yes/
yes
odd
pair
ed82
EYe
sT
issu
em
orph
ogen
esis
;n
euru
lati
on[i
nte
ract
sw
ith
Hh
path
way
]
AC
C,a
gen
esis
,dys
gen
esis
,or
hyp
opla
sia
ofth
eco
rpus
callo
sum
;DV
,dor
sal-v
entr
al;U
P,un
char
acte
rize
dP
-ele
men
tin
sert
ion
inth
ege
ne;
NP,
nea
rby
Pel
emen
ts;N
one,
no
mut
ants
and
no
Pel
emen
tskn
own
tobe
nea
rby;
R,
fun
ctio
nas
sess
edby
doub
le-s
tran
ded
RN
Ain
terf
eren
ce;
N,
beh
avio
ral
and/
orn
euro
anat
omic
alph
enot
ype
resu
lts
from
disr
upti
onby
mut
atio
nor
RN
Ai;
Hh
,h
edge
hog
;N
MJ,
neu
rom
uscu
lar
jun
ctio
n;
RT
K,
rece
ptor
tyro
sin
eki
nas
e.?,
prec
edes
phen
otyp
essu
gges
ted
but
not
con
clus
ivel
yde
mon
stra
ted.
aSe
eap
pen
dix
for
alte
rnat
ege
ne
sym
bols
.N
umbe
rsin
pare
nth
eses
follo
win
gin
divi
dual
gen
esre
fer
tore
pres
enta
tive
refe
ren
ces
from
the
mam
mal
ian
and
Dro
soph
ilage
net
ics
liter
atur
e:(1
)K
uts
che
etal
.(20
00);
Wer
ner
and
Man
seau
(199
7);(
2)B
on
det
al.(
2002
);W
akefi
eld
etal
.(20
01);
(3)
Jaco
bsen
etal
.(19
99);
Peri
zan
dFo
rtin
i(1
999)
;(4)
Gib
bon
san
dH
igg
s(2
000)
;(5)
Can
tan
ian
dG
agli
esi
(199
8);N
ewfe
ldan
dT
akae
su(2
002)
;Mar
eket
al.(
2000
);(6
)Fr
ioco
urt
etal
.(20
03);
(7)
Aka
bosh
iet
al.
(200
0);
Gio
rdan
oet
al.
(199
9);
(8)
An
der
son
etal
.(2
002)
;G
reen
eran
dR
obe
rts
(200
0);
(9)
Pass
os-
Bu
eno
etal
.(1
999)
;K
lam
btet
al.
(199
2);
Gar
cia-
Alo
nso
etal
.(2
000)
;Sh
ish
ido
etal
.(1
997)
;(1
0)Fo
xet
al.
(199
8);
Li
etal
.(1
999)
;D
ubn
auet
al.
(200
3);
(11)
Irw
inet
al.
(200
0);
Zh
ang
etal
.(2
001)
;D
ock
end
orf
fet
al.
(200
2);
Ish
izu
kaet
al.
(200
2);
Mo
rale
set
al.
(200
2);
C.
Mic
hel
,R
.K
raft
,B
.H
assa
nan
dL
.R
esti
fo(u
npu
blis
hed
resu
lts)
;(1
2)V
arg
ha-
Kh
adem
etal
.(1
998)
;(1
3)B
ien
ven
uet
al.
(199
8);
Ric
ard
etal
.(2
001)
;(1
4)E
lso
net
al.
(200
2);
Hu
ang
and
Ku
nes
(199
8);
(15)
Ald
red
and
Tre
mba
th(2
000)
;C
on
no
lly
etal
.(1
996)
;C
hyb
etal
.(1
999)
;W
olf
gan
get
al.
(200
1);(
16)
Li
etal
.(2
001)
;Nak
ato
etal
.(1
995)
;T
sud
aet
al.
(199
9);
(17)
Rei
sset
al.(
2001
);W
ittl
eet
al.
(199
9);(
18)
Lu
oet
al.
(200
2);K
ug
ler
and
Lak
om
ek(2
000)
;see
FlyB
ase
IDFB
gn00
0307
4;(1
9)B
oke
lan
dB
row
n(2
002)
;Peg
ora
roet
al.(
2002
);H
oan
gan
dC
hib
a(1
998)
;(20
)W
oo
lfen
den
etal
.(19
99);
Kra
ntz
etal
.(1
998)
;T
sai
etal
.(2
001)
;G
uet
al.
(199
5);
Flem
ing
etal
.(1
990)
;(2
1)W
elle
ran
dG
artn
er(2
001)
;G
arci
a-A
lon
soet
al.
(200
0);
Hal
lan
dB
iebe
r(1
997)
;(2
2)Jo
nes
etal
.(2
001)
;M
arti
net
al.
(199
9);
(23)
Car
do
soet
al.
(200
2);
Liu
etal
.(2
000)
;(2
4)C
ox
etal
.(2
000)
;B
rod
yet
al.
(200
2);
(25)
San
alet
al.
(200
0);
Tak
agis
hi
etal
.(19
96);
Mac
Iver
etal
.(19
98);
(26)
Lyn
chan
dG
utm
ann
(200
2);Y
ager
etal
.(20
01);
Gu
oet
al.(
2000
);(2
7)D
ou
gla
set
al.(
2003
);(2
8)L
inet
al.(
1998
);(2
9)B
illu
art
etal
.(1
998,
2001
);(3
0)B
ien
ven
uet
al.
(200
0);A
llen
etal
.(1
998)
;H
ing
etal
.(1
999)
;(3
1)M
oli
nar
iet
al.
(200
2);
(32)
Mar
shet
al.
(199
8);
Li
etal
.(2
003)
;O
ldh
amet
al.
(200
2);(
33)
Mu
san
teet
al.
(200
3);P
erki
ns
etal
.(1
996)
;(34
)Ja
cqu
ot
etal
.(2
002)
;G.P
utz
,T.Z
ars
and
M.H
eise
nbe
rg(p
erso
nal
com
mun
icat
ion
);(3
5)O
den
tet
al.
(199
9);
Ing
ham
and
McM
aho
n(2
001)
;(3
6)Pa
squ
ier
etal
.(2
000)
;Se
imiy
aan
dG
ehri
ng
(200
0);
(37)
Lau
mo
nn
ier
etal
.(2
002)
;B
ues
cher
etal
.(2
002)
;O
vert
on
etal
.(2
002)
;(38
)Pa
rvar
iet
al.
(200
2);M
arti
net
al.(
2002
);(3
9)M
izu
gu
chi
and
Tak
ash
ima
(200
1);T
apo
net
al.(
2001
);C
anal
etal
.(1
998)
;(40
)C
layt
on
-Sm
ith
and
Laa
n(2
003)
;(4
1)B
row
net
al.
(200
1);
Nag
aiet
al.
(200
0);
Cim
bora
and
Sako
nju
(199
5).
bA
ddit
ion
aldi
sord
ers
may
beca
used
bym
utat
ion
ofth
ese
gen
es;
see
the
appe
nd
ix.
cB
ased
onn
euro
path
olog
y,n
euro
phys
iolo
gy,
and/
orbr
ain
imag
ing
ofh
uman
pati
ents
.In
som
eca
ses,
data
from
mou
sem
utan
tsw
ere
also
con
side
red.
dYe
s/ye
s,m
ouse
mut
ant
disp
lays
an
euro
logi
cal
orbe
hav
iora
lph
enot
ype
rele
van
tto
MR
;ye
s/?,
mou
sem
utan
th
asn
otye
tbe
ench
arac
teri
zed
neu
rolo
gica
lly;
yes/
no,
mou
sem
utan
th
asn
okn
own
neu
rolo
gica
lph
enot
ype;
non
e,n
om
ouse
mut
ant.
eT
he
Dro
soph
ilage
nes
wit
hpr
efixe
s“C
G”
and
“EG
”h
ave
been
iden
tifi
edon
lyby
gen
ome
sequ
enci
ng
proj
ects
(see
FlyB
ase
ath
ttp:
//fl
ybas
e.bi
o.in
dian
a.ed
u/fo
rde
tails
).Se
eap
pen
dix
for
BL
AST
PE-
valu
es.
fB
iolo
gica
lfu
nct
ion
sin
brac
kets
are
infe
rred
from
mol
ecul
arda
ta(i
ncl
udin
gge
ne
expr
essi
onan
dbi
och
emis
try)
orse
quen
ceh
omol
ogy
topr
otei
ns
ofkn
own
fun
ctio
n.
All
oth
ers
are
base
don
mut
ant
phen
otyp
es.
849Molecular Genetics of Mental Retardation
The role of D. melanogaster in MR research: In terms a ligand of Notch (the Drosophila ligand is Serrate).The biological relevance of genetic interactions in hu-of primary amino acid sequence and protein-domain orga-
nization, the degree of MR gene conservation between man MR is well demonstrated by some of the Bardet-Biedl syndromes (BBS2 and BBS6; see appendix) inhumans and Drosophila is remarkable (Figure 1; appen-
dix). Not only individual genes but also whole pathways which clinical manifestations result from “triallelic in-heritance,” homozygosity at one locus and heterozygos-have been retained through �700 million years of evolu-
tion. These include protein glycosylation (ALG3, ALG6, ity at another (Katsanis et al. 2001). Genetic interactiontests in Drosophila could help clarify the functionalB4GALT1, DPM1, FUCT1, GCS1, MGAT2, MPDU1, PMI,
PPM2), as well as signaling pathways, notably the Hedge- relevance of the physical interaction between mamma-lian ZIC2 and GLI3 proteins (Koyabu et al. 2001).hog pathway (SHH, PTCH, PTCH2, GLI3, GPC3) and those
mediated by small G proteins (ARHGEF6, GDI1, OPHN1, The number of MR genes is very large, but they may beinvolved in a relatively small number of interconnectedPAK3, FGD1, GPH, RSK2, and others).
Given this remarkable conservation of MR genes, we pathways. If so, a modest number of pharmacologicaltreatment strategies might be effective for many MRpropose that Drosophila genetics can be used in a sys-
tematic manner to study MR. We have selected 42 fly patients. In fact, some types of acquired MR might bene-fit from the same drugs. Diagnoses of hereditary MR aregenes (the orthologs of 43 human MR genes) as “prime
candidates” for such analyses (Table 3). These genes typically made early in life at a time when developmentalbrain plasticity provides an opportunity for therapeuticmost likely act selectively within the brain during devel-
opment to establish the anatomical and physiological intervention. The widespread functional conservationof MR genes in Drosophila indicates that this geneticsubstrates for experience-dependent plasticity. The ma-
jority of prime-candidate orthologs currently have fly model system could play a critical role in the discoveryof novel treatment strategies for MR.mutants available (about the same fraction as have
mouse mutants available) and the rest can be mutagen- The authors thank Brian Blood for recent literature searches andized through the mobilization of nearby transposable BLAST analyses to update the list of human MR genes and their
Drosophila homologs. The authors are grateful to colleagues Davidelements or studied using RNA interference methodsMount for advice on bioinformatics methods, Terrill Yuhas and Nirav(Adams and Sekelsky 2002). About half are alreadyMerchant for computer support, Charles Hedgecock for assistanceknown to have neural phenotypes, behavioral or ana-with computer graphics, and John Meaney and Robert Erickson for
tomical, in Drosophila (Table 3 and references therein). helpful discussions about human genetic disease. This work wasThe anatomical defects involve neurons (e.g., cubitus funded by the National Institutes of Health (grant no. P01 NS028495).interruptus), glia (e.g., Neurofibromin 1), and neural pre-
Note added in proof: Evaluation of recently updated OMIM entriescursor cells (e.g., division abnormally delayed) and resultrevealed three more MR genes whose molecular identifications werefrom problems with proliferation (e.g., hedgehog), migra-published prior to September 30, 2003. They are AAAS (OMIM
tion (e.g., breathless), and process extension or arboriza- 605378), COH1 (OMIM 607817), and MLC1 (OMIM 605908).tion (e.g., Pak, dfmr1). For a few genes, neuronal defectsin the mushroom bodies, an arthropod learning andmemory center (Zars 2000), have been demonstrated LITERATURE CITED(e.g., Lissencephaly 1; Drosophila fragile-X mental retarda-
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ion
AM
TA
min
omet
hyl
tran
sfer
ase
3pG
lyci
ne
ence
phal
opat
hy
2383
10T
ran
sfer
ase
Met
abol
ic(a
min
oac
id):
CG
6415
0032
287
�10
0M
R2
neu
ro/g
lial
toxi
city
(neu
rotr
ansm
issi
on)
AR
G1
Arg
inas
e6q
Arg
inin
emia
2078
00H
ydro
lase
Met
abol
ic(u
rea
cycl
e):
argi
nase
0023
535
�60
MR
2sy
stem
icto
xici
tyA
RH
GEF
6R
ho
guan
ine
nuc
leot
ide
Xq
MR
X46
3002
67R
ecep
tor
Sign
alin
gpa
thw
ayrt
GEF
(&¶
)00
1580
3�
90(P
IXA
)ex
chan
gefa
ctor
6si
gnal
ing
(in
tegr
in):
neu
ron
alpr
otei
nde
velo
pmen
t/pl
asti
city
AR
SAA
ryls
ulfa
tase
A22
qM
etac
hro
mat
ic25
0100
Hyd
rola
seL
ysos
omal
path
way
CG
3219
1,00
5219
1�
23le
ukod
ystr
oph
y(g
lyco
lipid
):M
R2
oth
ers
(*)
loca
lto
xici
ty(g
lia:
mye
lin)
AR
XA
rist
ales
s-re
late
dX
pM
RX
36;W
est
syn
drom
e;30
0382
Tra
nsc
ript
ion
CN
Sde
velo
pmen
t/Pv
uII-P
stI
0023
489
�29
hom
eobo
x,X
-lin
ked
Part
ingt
onsy
ndr
ome;
regu
lato
rfu
nct
ion
:n
euro
nal
hom
olog
y13
,lis
sen
ceph
aly
mig
rati
onot
her
sA
SAH
N-A
cyls
phin
gosi
ne
8pFa
rber
2280
00H
ydro
lase
Lys
osom
alpa
thw
ayN
one
——
amid
ohyd
rola
selip
ogra
nul
omat
osis
(gly
colip
id):
MR
2(c
eram
idas
e)lo
calt
oxic
ity
(neu
ron
)
(con
tinue
d)
857Molecular Genetics of Mental Retardation
AP
PE
ND
IX
(Con
tinu
ed)
Mol
ecul
ar-
Gen
eC
hr.
OM
IMfu
nct
ion
GO
Dro
soph
ilaFl
yBas
eB
LA
STP
sym
bola
Gen
en
ame
arm
bC
linic
aldi
sord
erc
no.
cate
gory
dB
iolo
gica
lfu
nct
ion
(s)e
hom
olog
(s)f
no.
gE
-val
ueh
ASL
Arg
inin
osuc
cin
ate
lyas
e7q
Arg
inin
osuc
cin
i-20
7900
Lya
seM
etab
olic
(ure
acy
cle)
:C
G95
1000
3207
6�
106
caci
duri
aM
R2
syst
emic
toxi
city
ASP
AA
spar
toac
ycla
se17
pC
anav
andi
seas
e27
1900
Hyd
rola
seM
etab
olic
:gl
ial
Non
e—
—de
velo
pmen
t/fu
nct
ion
;M
R2
loca
lto
xici
ty(m
yelin
)A
SPM
Abn
orm
alsp
indl
e-lik
e,1q
Prim
ary
mic
roce
phal
y5
6054
81Pr
otei
nbi
ndi
ng
CN
Sde
velo
pmen
t/ab
norm
al00
0014
0�
54m
icro
ceph
aly-
fun
ctio
n:
spin
dle
(&¶
)as
soci
ated
neu
roge
nes
isA
SSA
rgin
inos
ucci
nat
e9q
Cla
ssic
citr
ullin
emia
6034
70L
igas
eM
etab
olic
(ure
acy
cle)
:B
G:D
S000
04.1
400
2656
5�
121
syn
thet
ase
(typ
eI)
MR
2sy
stem
icto
xici
tyA
TP2
A2
AT
Pase
,C
a(2
) -12
qD
arie
r-W
hit
edi
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8740
Tra
nsp
orte
rSi
gnal
ing
path
way
Cal
cium
AT
Pase
at00
0455
1�
300
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spor
tin
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alci
um):
cell
60A
(&¶
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ow-tw
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adh
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kin
);M
Rca
use
unkn
own
AT
P7A
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-tran
spor
tin
gX
qM
enke
ssy
ndr
ome;
3000
11T
ran
spor
ter
Met
abol
ic:
CN
SC
G18
86(&
)00
3034
3�
300
AT
Pase
,�
-pol
ypep
tide
occi
pita
lh
orn
deve
lopm
ent/
syn
drom
efu
nct
ion
AT
RA
taxi
a-te
lan
giec
tasi
aan
d3q
Seck
elsy
ndr
ome
6012
15K
inas
eD
NA
repa
ir:
CN
Sm
ei-4
1(&
)00
0436
7�
300
RA
D3-
rela
ted
deve
lopm
ent/
fun
ctio
nA
TR
X(X
H2,
X-li
nke
dh
elic
ase
2X
q�
-Th
alas
sem
ia/M
R30
0032
Hel
icas
eC
hro
mos
ome
stru
ctur
eX
NP
(&¶
)00
3933
8�
300
XN
P)sy
ndr
ome;
non
spec
ific
and
tran
scri
ptio
nM
R;
oth
ers
regu
lati
onA
VPR
2A
rgin
ine
vaso
pres
sin
Xq
X-li
nke
dn
eph
roge
nic
3048
00R
ecep
tor
Sign
alin
gpa
thw
ayC
G61
11,
oth
ers
(*)
0039
396
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rece
ptor
2di
abet
esin
sipi
dus
(GPC
R):
MR
2sy
stem
icto
xici
tyB
4GA
LT
1�
-1,4
-9p
Con
gen
ital
diso
rder
of13
7060
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nsf
eras
ePr
otei
nm
odifi
cati
onB
cDN
A:G
H13
356,
0027
538
�60
Gal
acto
sylt
ran
sfer
ase
1gl
ycos
ylat
ion
type
IId
(gly
cosy
lati
on):
CN
SC
G14
517
deve
lopm
ent/
fun
ctio
nB
4GA
LT
7�
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-5q
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lers
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los
syn
drom
e,60
4327
Tra
nsf
eras
ePr
otei
nm
odifi
cati
onC
G11
780
(&)
0039
258
�73
(XG
PT1)
Gal
acto
sylt
ran
sfer
ase
7pr
oger
oid
form
(gly
cosy
lati
on):
?CN
Sde
velo
pmen
t/fu
nct
ion
BB
S1B
arde
t-Bie
dlsy
ndr
ome
111
qB
arde
t-Bie
dlsy
ndr
ome
120
9901
Un
know
nU
nkn
own
CG
1482
500
3574
1�
62fu
nct
ion
BB
S2B
arde
t-Bie
dlsy
ndr
ome
216
qB
arde
t-Bie
dlsy
ndr
ome
260
6151
Un
know
nU
nkn
own
Non
e—
—fu
nct
ion
(con
tinue
d)
858 J. K. Inlow and L. L. Restifo
AP
PE
ND
IX
(Con
tinu
ed)
Mol
ecul
ar-
Gen
eC
hr.
OM
IMfu
nct
ion
GO
Dro
soph
ilaFl
yBas
eB
LA
STP
sym
bola
Gen
en
ame
arm
bC
linic
aldi
sord
erc
no.
cate
gory
dB
iolo
gica
lfu
nct
ion
(s)e
hom
olog
(s)f
no.
gE
-val
ueh
BB
S4B
arde
t-Bie
dlsy
ndr
ome
415
qB
arde
t-Bie
dlsy
ndr
ome
460
0374
[Tra
nsf
eras
e]?P
rote
inC
G13
232
(&)
0033
578
�54
mod
ifica
tion
(gly
cosy
lati
on):
MR
caus
eun
know
nB
BS6
Bar
det-B
iedl
syn
drom
e6
20p
Bar
det-B
iedl
syn
drom
e6
6048
96C
hap
eron
ePr
otei
nm
odifi
cati
onT
cp1-
like,
Cct
�(*
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0367
6�
11(M
KK
S)(f
oldi
ng)
:M
Rca
use
unkn
own
BC
KD
HA
Bra
nch
ed-c
hai
nke
toac
id19
qM
aple
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pur
ine
2486
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xido
redu
ctas
eM
etab
olic
(am
ino
acid
):C
G81
99(&
)00
3770
9�
136
deh
ydro
gen
ase
E1�
dise
ase
type
IAM
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syst
emic
and
loca
lto
xici
tyB
CK
DH
BB
ran
ched
-ch
ain
keto
acid
6pM
aple
syru
pur
ine
2486
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xido
redu
ctas
eM
etab
olic
(am
ino
acid
):C
G17
691
(&)
0039
993
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4de
hyd
roge
nas
eE
1�di
seas
ety
peIB
MR
2sy
stem
ican
dlo
cal
toxi
city
BC
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Yeas
tB
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hom
olog
-like
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ucle
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etab
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(oxi
dati
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G49
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ence
phal
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hy,
and
bin
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g]ph
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n):
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ipin
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ardi
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nkn
own
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nit
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trop
hy
fun
ctio
nfu
nct
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ypot
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amic
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tuit
ary
axis
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DB
artt
in1p
Bar
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syn
drom
ew
ith
6064
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ran
spor
ter
MR
caus
eun
know
n:
Non
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nso
rin
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ldea
fnes
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mic
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city
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DB
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nid
ase
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ulti
ple
carb
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2532
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etab
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ious
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Rva
nin-
like,
oth
ers
0040
069
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defi
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emic
and
loca
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bon
ican
hyd
rase
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eope
tros
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ith
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on,
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ers
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omoc
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ia23
6200
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seM
etab
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NS
CG
1753
0031
148
�16
3de
velo
pmen
t/fu
nct
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stem
ican
dlo
cal
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city
CG
I58
Com
para
tive
gen
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Ich
thyo
tic
neu
tral
lipid
6047
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lase
Met
abol
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atty
acid
):C
G18
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6�
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enti
fica
tion
58st
orag
edi
seas
e?M
R2
loca
lto
xici
ty
(con
tinue
d)
859Molecular Genetics of Mental Retardation
AP
PE
ND
IX
(Con
tinu
ed)
Mol
ecul
ar-
Gen
eC
hr.
OM
IMfu
nct
ion
GO
Dro
soph
ilaFl
yBas
eB
LA
STP
sym
bola
Gen
en
ame
arm
bC
linic
aldi
sord
erc
no.
cate
gory
dB
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gica
lfu
nct
ion
(s)e
hom
olog
(s)f
no.
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-val
ueh
CIA
S1C
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yrin
1qC
hro
nic
neu
rolo
gic
6064
16A
popt
osis
?Sig
nal
ing
path
way
Non
e—
—cu
tan
eous
and
regu
lato
r(u
nkn
own
):im
mun
ear
ticu
lar
syn
drom
ere
spon
se;
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2in
flam
mat
ion
CK
N1
(CSA
)C
ocka
yne
syn
drom
ety
peI
5qC
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yne
syn
drom
e21
6400
Tra
nsc
ript
ion
DN
Are
pair
(tra
n-
[will
die
slow
ly,
0040
066
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type
Ifa
ctor
scri
ptio
n-c
oupl
ed):
oth
ers]
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Sde
velo
pmen
t/fu
nct
ion
(mye
lin)
CL
CN
KB
Ch
lori
dech
ann
el,
1pB
artt
ersy
ndr
ome
6020
23T
ran
spor
ter
MR
caus
eun
know
n:
CG
3111
6(&
)00
5111
6�
108
kidn
ey,
Bty
peII
I?s
yste
mic
toxi
city
CL
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itoy
l-pro
tein
1pN
euro
nal
cero
id60
0722
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rola
seL
ysos
omal
path
way
Ppt1
(&)
0030
057
�74
(PPT
1)th
ioes
tera
se1
ipof
usci
nos
is,
(lip
opro
tein
):M
R2
infa
nti
lelo
calt
oxic
ity
(neu
ron
)C
LN
2C
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dlip
ofus
cin
osis
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euro
nal
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id20
4500
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rola
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ysos
omal
path
way
Non
e—
—n
euro
nal
2lip
ofus
cin
osis
,la
te(p
epti
de):
MR
2lo
cal
infa
nti
leto
xici
ty(n
euro
n)
CL
N3
Cer
oid
lipof
usci
nos
is,
16p
Bat
ten
dise
ase
6070
42U
nkn
own
Lys
osom
alpa
thw
ay:
MR
CG
5582
0036
756
�69
neu
ron
al3
fun
ctio
n2
loca
lto
xici
ty(n
euro
n);
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apti
cfu
nct
ion
CL
N5
Cer
oid
lipof
usci
nos
is,
13q
Neu
ron
alce
roid
2567
31U
nkn
own
Lys
osom
alpa
thw
ay:
MR
Non
e—
—n
euro
nal
5lip
ofus
cin
osis
,la
tefu
nct
ion
2lo
cal
toxi
city
infa
nti
le(n
euro
n)
CL
N6
Cer
oid
lipof
usci
nos
is,
15q
Neu
ron
alce
roid
6067
25U
nkn
own
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osom
alpa
thw
ay:M
RN
one
——
neu
ron
al6
lipof
usci
nos
is,
late
fun
ctio
n2
loca
lto
xici
tyin
fan
tile
(neu
ron
)C
LN
8C
eroi
dlip
ofus
cin
osis
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ress
ive
epile
psy
6001
43U
nkn
own
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osom
alpa
thw
ay:M
RN
one
——
neu
ron
al8
wit
hM
Rfu
nct
ion
2lo
cal
toxi
city
(neu
ron
)C
OX
10C
ytoc
hro
me
cox
idas
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pPr
ogre
ssiv
e60
2125
Tra
nsf
eras
eM
etab
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(oxi
dati
veC
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3700
3222
2�
80su
bun
it10
mit
och
ondr
ial
phos
phor
ylat
ion
):M
Ren
ceph
alop
ath
y2
loca
len
ergy
defi
cien
cyC
PS1
Car
bam
oylp
hos
phat
e2q
Hyp
eram
mon
emia
due
2373
00L
igas
eM
etab
olic
(ure
acy
cle)
:ru
dim
enta
ry00
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9�
300
syn
thet
ase
1to
CPS
1de
fici
ency
MR
2sy
stem
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xici
tyC
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BP
CR
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din
gpr
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n16
pR
ubin
stei
n-T
aybi
6001
40T
ran
scri
ptio
nT
ran
scri
ptio
nne
jire
(&¶
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1562
4�
300
(CB
P)sy
ndr
ome
regu
lato
rre
gula
tion
:C
NS
deve
lopm
ent/
fun
c-ti
on;
?ch
rom
osom
est
ruct
ure
(con
tinue
d)
860 J. K. Inlow and L. L. Restifo
AP
PE
ND
IX
(Con
tinu
ed)
Mol
ecul
ar-
Gen
eC
hr.
OM
IMfu
nct
ion
GO
Dro
soph
ilaFl
yBas
eB
LA
STP
sym
bola
Gen
en
ame
arm
bC
linic
aldi
sord
erc
no.
cate
gory
dB
iolo
gica
lfu
nct
ion
(s)e
hom
olog
(s)f
no.
gE
-val
ueh
CX
OR
F5C
hro
mos
ome
XX
pO
ral-f
acia
l-dig
ital
3001
70[P
rote
inC
NS
deve
lopm
ent/
Non
e—
—op
enre
adin
gfr
ame
5sy
ndr
ome
type
Ibi
ndi
ng]
fun
ctio
n:
neu
ron
alm
igra
tion
/di
ffer
enti
atio
n(?
mic
rotu
bule
)C
YP27
A1
Cyt
och
rom
eP4
5027
A1
2qC
ereb
rote
ndi
nou
s60
6530
Oxi
dore
duct
ase
Met
abol
ic(l
ipid
):M
R2
Cyp
49a1
,ot
her
s00
3352
4�
42(s
tero
l27
-hyd
roxy
lase
)xa
nth
omat
osis
syst
emic
and
loca
lto
xici
tyD
BT
Dih
ydro
lipoa
mid
e1p
Map
lesy
rup
urin
e24
8610
Tra
nsf
eras
eM
etab
olic
(am
ino
acid
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rich
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deve
lopm
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ctio
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(con
tinue
d)
862 J. K. Inlow and L. L. Restifo
AP
PE
ND
IX
(Con
tinu
ed)
Mol
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ar-
Gen
eC
hr.
OM
IMfu
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Dro
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e):
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Sde
velo
pmen
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tinue
d)
863Molecular Genetics of Mental Retardation
AP
PE
ND
IX
(Con
tinu
ed)
Mol
ecul
ar-
Gen
eC
hr.
OM
IMfu
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defi
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and
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deve
lopm
ent/
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(con
tinue
d)
864 J. K. Inlow and L. L. Restifo
AP
PE
ND
IX
(Con
tinu
ed)
Mol
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ar-
Gen
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hr.
OM
IMfu
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Dro
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sym
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en
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ron
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tran
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ter
Prot
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9620
0037
567
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lyco
syla
tion
):C
NS
deve
lopm
ent/
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lyco
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LT
Gal
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865Molecular Genetics of Mental Retardation
AP
PE
ND
IX
(Con
tinu
ed)
Mol
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hr.
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¶)
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ty
(con
tinue
d)
866 J. K. Inlow and L. L. Restifo
AP
PE
ND
IX
(Con
tinu
ed)
Mol
ecul
ar-
Gen
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hr.
OM
IMfu
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GO
Dro
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Gen
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tinue
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867Molecular Genetics of Mental Retardation
AP
PE
ND
IX
(Con
tinu
ed)
Mol
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ar-
Gen
eC
hr.
OM
IMfu
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d)
868 J. K. Inlow and L. L. Restifo
AP
PE
ND
IX
(Con
tinu
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Mol
ecul
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hr.
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ND
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hr.
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hr.
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AP
PE
ND
IX
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Mol
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hr.
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Dro
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AP
PE
ND
IX
(Con
tinu
ed)
Mol
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ar-
Gen
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hr.
OM
IMfu
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AP
PE
ND
IX
(Con
tinu
ed)
Mol
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ar-
Gen
eC
hr.
OM
IMfu
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ND
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hr.
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Dro
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ino
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emic
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acid
indu
ced
117
pSm
ith
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enis
6076
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ptio
nre
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syn
drom
ere
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tor]
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NS
deve
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men
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eu-
ron
diff
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tiat
ion
(con
tinue
d)
877Molecular Genetics of Mental Retardation
AP
PE
ND
IX
(Con
tinu
ed)
Mol
ecul
ar-
Gen
eC
hr.
OM
IMfu
nct
ion
GO
Dro
soph
ilaFl
yBas
eB
LA
STP
sym
bola
Gen
en
ame
arm
bC
linic
aldi
sord
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cate
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men
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(con
tinue
d)
878 J. K. Inlow and L. L. Restifo
AP
PE
ND
IX
(Con
tinu
ed)
Mol
ecul
ar-
Gen
eC
hr.
OM
IMfu
nct
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GO
Dro
soph
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Gen
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(&)
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diff
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tiat
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(con
tinue
d)
879Molecular Genetics of Mental Retardation
AP
PE
ND
IX
(Con
tinu
ed)
Mol
ecul
ar-
Gen
eC
hr.
OM
IMfu
nct
ion
GO
Dro
soph
ilaFl
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LA
STP
sym
bola
Gen
en
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arm
bC
linic
aldi
sord
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no.
cate
gory
dB
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hom
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TD
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