a small number of defective mutations in the pseudogene that can replace the analogous sequences of functional 21-OH genes. Comparison of the CYP2lA and CYP2lB gene sequences reveals only about 80 nucleotide differ- ences out of a total of about 3300. Of these, many map within the second intron at positions that are unlikely to have a significant effect on gene expres- sion. In addition, several differences that map within exons do not cause an amino acid replacement or result in an amino acid replacement that would be expected to have a minimal effect on gene expression. Consequently, identi- fication of the small number of addi- tional mutations in the CYP2lA pseudo- gene that are associated with defective gene expression can be achieved by monitoring the in vitro expression of cloned CYP2 1B genes that have been mutated in vitro at candidate sites (Higashi et al. 1988b). Such information will permit rapid prenatal diagnosis and reliable carrier tests for 21-OH de- ficiency through the identification of 21-OH-deficient haplotypes by in vitro amplification of mutated 21-OH genes and their subsequent analysis for the presence of defective mutations nor- mally associated with the CYP21A pseudogene (Collier et al. 1989).

References

Amor M, Parker KL, Globerman H, New MI, White PC: Mutation in the CYP2lB gene (Be-l 72->Asn) causes steroid 2 1 -hydroxy- lase deficiency. Proc Nat1 Acad Sci USA 1988; 85:1600.

Collier S, Sinnott PJ, Dyer PA, Price DA, Harris R, Strachan T: Pulsed field gel electrophoresis identifies a high degree of variability in the number of tandem 21- hydroxylase and complement C4 gene re- peats in 21-hydroxylase deficiency haplo- types. EMBO J 1989; 8:1393.

Globerman H, Amor M, Parker KL, New MI, White PC: Nonsense mutation causing ste- roid 21-hydroxylase deficiency. J Clin In- vest 1988; 82:139.

Harada F, Kimura A, Iwanaga T, Shimozawa K, Yata J, Sasazuki T: Gene conversion- like events cause steroid 21-hydroxylase deficiency in congenital adrenal hyperpla- sia. Proc Nat1 Acad Sci USA 1987; 84:8091.

Higashi Y, Yoshioka H, Yamane M, Gotoh 0, Fujii-Kuriyama Y: Complete nucleotide sequence of 2 steroid 2 1 -hydroxylase genes tandemly arranged in human chromo- some: a pseudogene and a genuine gene. Proc Nat1 Acad Sci USA 1986; 83:2841.

Higashi Y, Tanae A, moue H, Fujii-Kuriyama

Y: Evidence for frequent gene conversion in the steroid 21-hydroxylase P-45O(C21) gene: implications for steroid 21.hydroxy- lase deficiency. Am J Hum Genet 1988a; 42:17.

Higashi Y, Tanae A, Inoue H, Hirosama T, Fujii-Kuriyama Y: Aberrant splicing and missense mutations cause steroid 2 l- hydroxylase [P-45O(C21)] deficiency in hu- mans: possible gene conversion products. Proc Nat1 Acad Sci USA 1988b; 85:7486.

Miller WL: Gene conversions, deletions and polymorphisms in congenital adrenal hy- perplasia. Am J Hum &net 1988; 42:4.

Rodrigues NR. Dunham I, Yu CY, Carroll MC, Porter RR, Campbell RD: Molecular

characterization the HLA-linked xtc~r.c~~cl 21.hydroxylase B gene Iron1 an individual with congenital adrenal 11) pcrplasia. EMBO J 1987; 6:1653.

Speiscr PW, New Ml, White PC: Molecular genetic analysis of non-classical steroid 21.hydroxylase deficiency associated with HLLA-Bl4,DRl. N Enpl J Med 1988: 319:19.

White PC, New MI, DuPont 8: Str-ucture ot human steroid 21-hydroxvlase genes. Proc Nat1 Acad Sci USA 1986; 83:511 I.

White PC, Vitek, DuPont B, New Ml: Charac- terization of frequent deletions causing steroid 21.hydroxylasc deficiency. Proc Nat1 Acad Sci USA 1988; 85:4436. TEM

Receptor-Effector Coupling by G-Proteins Implications for Endocrinology Allen M. Spiegel

Discovered serendipitously in the course of studies on the mecha- nism of glucagon stimulation of hepatic cyclic AMP formation, G-proteins have emerged as an expanding family of signal transduc- ers, coupling diverse receptors and effecters. Quantitative andlor qualitative changes in G-proteins may profoundly affect hormone action, and can lead to clinically apparent endocrine dysfunction.

?? G-Proteins: General Features of Structure and Function

G-proteins involved in signal transduc- tion are members of a guanine nucleo- tide-binding protein superfamily that includes cytoskeletal proteins such as tubulin, soluble proteins (initiation and elongation factors involved in protein synthesis), and low molecular weight GTP-binding proteins such as the ras p21 protooncogenes and ras-related proteins (Gilman 1987; Iyengar and Birnbaumer, 1987; Spiegel et al. 1988). Members of the G-protein subset of the GTP-binding protein superfamily share certain general features with

Allen M. Spiegel is at the Molecular Patho- physiology Branch, National Institute of Di- abetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

other members of the GTP-binding pro- tein superfamily: 1) all GTP-binding proteins bind guanine nucleotides with high affinity and specificity and possess intrinsic GTPase activity that modulates interactions between the GTP-binding protein and other ele- ments; and 2) GTP-binding proteins serve as substrates for ADP ribo- sylation by bacterial toxins-this co- valent modification disrupts normal function.

G-proteins share other features that distinguish them from other GTP-bind- ing proteins. These features include: 1) association with the cytoplasmic sur- face of the plasma membrane (ras p21 and some other low molecular weight GTP-binding proteins are also associ- ated with the cytoplasmic membrane surface); 2) function as receptor-effector couplers; and 3) heterotrimeric struc- ture (Figure 1). G-proteins contain o(-, /3-, and y-subunits, each distinct gene

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1st Messenger

2nd Messenger

intracellular

Figure 1. Schematic diagram of a generic G-protein-coupled receptor and effector. Extra- cellular “first messengers” interact with specific receptors (R) that are transmembrane glycoproteins. The receptor’s putative seven membrane-spanning domains, extracellular amino-terminus and three loops, and intracellular three loops plus carboxy-terminus are indicated. Activation of receptor by the first messenger leads to interaction with and activation of the heterotrimeric G-protein (G) associated with the cytoplasmic surface of the membrane. The G-protein in turn interacts with and regulates an effector (E) that generates an intracellular signal. Effecters may be transmembrane glycoproteins (e.g., adenylyl cyclase).

products. The latter two subunits are tightly, but noncovalently, linked in a /3y-complex. The a-subunits bind gua- nine nucleotide, serve as toxin sub- strates, confer specificity in receptor- effector coupling, and directly modu- late effector activity. On activation by GTP, a-subunits are thought to disso- ciate from the /Iy-complex (Figure 2). The latter is required for G-protein- receptor interaction, can inhibit G- protein activation by blocking o-sub- unit dissociation, and may in some cases directly regulate effector activity.

Receptors coupled to G-proteins share a common topographic structure based on hydrophobicity plots of pri- mary sequences predicted by cloned complementary DNAs (O’Dowd et al. 1989). One or more of the intracellular “loops” and the carboxyl-terminus (Figure 1) are the presumed sites of G-protein interaction. On coupling to the G-protein, receptors display a high affinity for agonists. The receptor un- coupled from the G-protein (after disso- ciation elicited by binding of GTP) dis- plays a lower affinity for agonists. This accounts for the ability of added gua- nine nucleotides to inhibit the binding of agonists (for example, see Glossman et al. 1974) that is characteristic of G-protein-coupled receptors.

?? Specific Features of G-Protein Structure and Function

Molecular cloning provides evidence for a minimum of eight distinct o-subunit genes: G,, G,, Gil, Giz, Gi3, G,l, Gu, (Gil- man 1987; Iyengar and Birnbaumer 1987; Spiegel et al. 1988), and G,(,, (Lochrie and Simon 1988). Further di- versity is created by alternative splic- ing, leading to the expression of four forms of G, (Bray et al. 1986). At least two distinct genes each exist for both p- and y-subunits. The expression of cer- tain o-subunits is highly restricted (e.g.,

G,, and Gu are found only in photo- receptor rod and cone cells, respec- tively), whereas others, such as G, and Glz, are expressed ubiquitously. Other G-proteins may show an intermediate range of distribution (e.g., G, is found principally in neural cells and endo- crine glands such as anterior pituitary and pancreatic islets). Peptide anti- bodies capable of distinguishing be- tween G-protein subtypes (e.g., be- tween the various pertussis toxin sub- strates) have been very helpful in defining the distribution of individual G-proteins (Goldsmith et al. 1988a, 1988b).

The specificity of G-protein interac- tions with receptors and effecters has been defined in very few cases (Table 1). Studies involving reconstitution of purified receptors and G-proteins in phospholipid vesicles showed that P-adrenergic receptors couple, in de- creasing order of efficiency, to Gs > G, >> G,, and that for rhodopsin, the se- lectivity of coupling is G, = G, >:> G, (Cerione et al. 1985). Similar studies involving G-protein-effector interac- tions indicated that only G, can activate adenylyl cyclase (G, also appears to stimulate another effector, a Ca*+ chan- nel) and that G, uniquely activates reti- nal cGMP phosphodiesterase (e.g., see Roof et al. 1985). The endogenous G- proteins coupled to most other recep- tors and effecters, however, remain to be identified. Many G-protein-coupled receptors (e.g., Dz-dopaminergic) (Seno- gles et al. 1987) and a variety of effec- tors, including adenylyl cyclase (inhibi- tion), certain Ca” (inhibition) and K’ (stimulation) channels, and phospholi- pase C in cell types such as neutrophils

Receptors* G-Proteins Effecters

Opsins P-adrenergic,

glucagon Somatostatin,

D2-dopaminergic

G,-rod, G,-cone G,

G’,, G,iz, Gf3, Gt

TRH, MI muscarinic

? ?

?

G z(x) ?

cGMP-phosphodiesterase Adenylyl cyclase (stimulation) Ca’+ channel (stimulation) Adenylyl cyclase (inhibition)t Ca’+ channel (inhibition)? K+ channel (stimulation)t Phospholipase C (stimulation)

Phospholipase A2 (stimulation)$

*Only selected examples are shown; tpertussis toxin-sensitive; $direct modulation by &J (?)

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Inactive

GTP

Activated Receptor Catalyzes Exchange

GDP

Active (Binds Effector)

Figure 2. The G-protein GTPase cycle. The o-subunits of G-proteins in their basal (inac- tive) state contain tightly bound GDP and are associated with the /+y-complex. Interaction with an activated receptor catalyzes the exchange of bound GDP for ambient GTP. Binding of GTP leads to dissociation of G-protein from the receptor and of the cu-sub- unit from the /3-y. GTP-bound cr interacts with and regulates the effector. Whether the &complex may also directly regulate certain effector activities is not clear. The intrinsic GTPase activity of the o-subunit leads to hydrolysis of bound GTP to GDP. This “turns off” the o-subunit; the latter dissociates from the effector and reassociates with the py-complex to reenter the GTPase cycle. Bacterial toxins transfer (dashed arrows) ADP ribosc from NAD to G-protein oc-subunits. Pertussis toxin (PT) leads to uncoupling of its G-protein substrates from receptors. This blocks signal transduction by preventing the exchange of GTP for GDP. Cholera toxin (CT) acts on G, to reduce its intrinsic rate of GTPase activity. This causes more long-lived G-protein (and, thereby, effector) activation.

(e.g., f-Met-Leu-Phe receptor), are regu- lated by one or more pertussis toxin- sensitive G-proteins (Gilman 1987; Iyengar and Birnbaumer 1987; Spiegel et al. 1988). Because not only both forms of G, but also G,,, G,z, Gi,, and G, are pertussis toxin-sensitive G-proteins, demonstration of an effect of pertussis toxin on receptor or effector regulation does not uniquely identify the relevant endogenous G-protein, In most cells, phospholipase C is regulated by a per- tussis toxin-insensitive G-protein. G,(,) may play this role, but definitive evi- dence is lacking. Phospholipase A1 ac- tivity may also be regulated by one or more G-proteins, perhaps by the &-complex. The latter has also been suggested to stimulate a K+ channel,

but recent evidence suggests this is an indirect effect (Kim et al. 1989).

?? Implications for Normal and Abnormal Endocrine Function

Numerous hormones act by binding to receptors that are coupled to effecters by G-proteins. Examples include virtu- ally all of the hypothalamic releasing- hormones, all of the anterior and poste- rior pituitary hormones, with the ex- ceptions of growth hormone and pro- lactin, and many other peptide hormones, monoamines, and prosta- glandins. G-proteins are directly impli- cated not only in the actions of many hormones, but also in the regulation of hormone synthesis and secretion (e.g.,

prolactin [Enjalbert ct al. 19861 and insulin [Sharp ct al. 19891 sccrction). hr a given cell, several lypes 01 lit51 meb- sengers may act through distinct G- protein-coupled pathways to regulate a physiologic action such as prolactin sc- cretion (Figure 3). A role for GTP-bincl- ing proteins in distal steps of hormone secretion (such as exocytosis) has also been identified, but the relevant GTP- binding proteins may belong to the lower molecular mass (-20 kDa) subset of the GTP-binding protein superfamily (Bourne 1988).

The actions of hormones whose re- ceptors are not known to be directly linked to G-proteins may nonetheless indirectly involve G-proteins. Steroid (Chang and Bourne 1987) and thyroid (Milligan et al. 1987) hormones may act in part by modulating synthesis of G- protein subunits. Although purified G- proteins may serve as high affinity sub- strates for tyrosine kinase-type recep- tors (Zick et al. 1986), evidence that this occurs in intact cells is still lacking. The ability of insulin to inhibit pertussis toxin-catalyzed ADP ribosylation of “Gi” in rat liver membranes, however, suggests that tyrosine kinase-type re- ceptors may interact in some manner with G-proteins (Rothenberg and Kahn 1988).

Because of their critical position in the pathway of hormone action, modi- fications of G-proteins can have a pro- found impact on signal transduction. Covalent modification of a-subunits by bacterial toxins (Figure 2) is a well- delined example. ADP ribosylation of “G,” by pertussis toxin uncouples the G-protein from the receptor, and leads to a form of hormone resistance; ADP ribosylation of G, by cholera toxin slows the intrinsic GTPase “turn-off” reaction and leads to constitutive (i.e., hormone-independent) activation of the transduction pathway. More generally, quantitative and/or qualitative changes that lead to the loss of G-protein func- tion can cause hormone resistance, whereas changes that cause consti- tutive G-protein activation lead to hor- mone-independent transmission of sec- ond messenger signals. Both acquired and genetic G-protein modifications can lead to abnormal signal transduc- tion and clinical disease. I will give selected examples of each type of G- protein abnormality.

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H2

physiologic effects

Figure 3. Diverse G-proteins mediate the physiologic effects of diverse hormones in a single cell type. The schematic diagram indicates three distinct receptors (R,, Rz, R,) that selectively bind three different first messengers (H,, HZ, H,). R, is coupled to stimulation (solid arrow with “+“) of adenylyl cyclase (AC) by C,. Rz is coupled to inhibition (dashed arrow) of adenylyl cyclase by “G,” and to regulation of ion channels by Gk (stimulation of certain K’ channels) and G, (inhibition of certain Ca*+ channels). The specific G-proteins linked to R,-type receptors have not been definitively identified, but because all of these actions are abolished by pertussis toxin, presumptive candidates include G,,. G,z, G,j, and G,. Whether Rz represents a single receptor subtype capable of coupling to multiple G-proteins or whether distinct subtypes of Rz exist for each G-protein has also not been established. Rj is linked by a pertussis toxin-insensitive (and as yet unidentified) G-protein to stimulation of phospholipase C, which generates the dual second messengers diacylglycerol (DAG) and inositol trisphosphate (IP,). Different pathways may predominate in a given cell, but in certain cells, each pathway may be utilized by distinct first messengers. In pituitary lactotrophs, for example, the physiologic effects (regulation of prolactin secretion) of VIP (stimulation), dopamine (inhibition), and TRH (stimulation) involve the R,, Rz, and R1 pathways, respectively.

Deficiency of G,-a (Carter et al. 1987) in the inherited disorder pseudohy- poparathyroidism type Ia leads to resis- tance to multiple agents that act by stimulating CAMP production. In con- trast, constitutive activation of Gs-(Y in some human growth hormone-secreting pituitary tumors (Vallar et al. 1987), presumably through a somatic point mutation (Bourne 1987), may lead to unregulated growth hormone secretion, and perhaps to the neoplastic state it- self. Unregulated hormone secretion and benign neoplasia could, in princi- ple, also result from loss of function of a G-protein that couples a pathway medi- ating inhibition of hormone release and cell division. Thus, failure to respond to dopamine (Figure 3) in certain rat pitui- tary tumors may be due to a relative deficiency of G, (Collu et al. 1988). Es- trogens, known to cause functional un- coupling of D,-dopamine receptors in anterior pituitary (Munemura et al. 1989), may act by decreasing the

amount of “inhibitory” G-proteins such as G,. Loss of inhibitory G-protein func- tion has also been reported in animal models of diabetes mellitus (Gawler et al. 1987), although the mechanism is unclear.

?? Current Questions and Future Directions

Fundamental aspects of G-protein structure and function remain unde- fined: 1) the mechanism of G-protein attachment to the plasma membrane, and the distribution of G-proteins in other subcellular compartments; 2) the regulation of G-protein gene expression, and coordinate regulation (if any) of subunit synthesis and assembly; 3) the relative importance of (Y- versus fly-sub- units in regulating effector function (e.g., in adenylyl cyclase inhibition); and 4) the identity of the pertussis toxin-insensitive G-protein that stimu- lates phospholipase C, and the specific- ity of receptor-effector coupling by the

various pertussis toxin-sensitive G- proteins.

Molecular biologic and immuno- chemical (Simonds et al. 1989) ap- proaches should help clarify these and related issues. It is likely that new G- proteins and new G-protein-regulated effecters remain to be discovered. Also, phosphorylations and other covalent modifications of G-proteins are likely to be identified; some may account for “cross-talk” between diverse transduc- tion pathways. Finally, as our knowl- edge of G-protein structure and func- tion increases, so does the likelihood that modifications of these key proteins will be discovered in various disease states.

References

Bourne H: Discovery of a new oncogene in pituitary tumors? Nature 1987; 330:517.

Bourne H: Do GTPases direct membrane traffic in secretion? Cell 1988; 53:669.

Bray P, Carter A, Simons C et al.: Human cDNA clones for four species of G-q signal transduction protein. Proc Nat1 Acad Sci USA 1986; 83:8893.

Carter A, Bardin C, Collins R, Simons C, Bray P, Spiegel A: Reduced expression of multiple forms of the a subunit of the stimulatory GTP-binding protein in pseu- dohypoparathyroidism type Ia. Proc Nat1 Acad Sci USA 1987; 84:7266.

Cerione RA, Staniszewski C, Benovic JL et al.: Specificity of the functional interac- tions of the P-adrenergic receptor and rho- dopsin with guanine nucleotide regulatory proteins reconstituted in phospholipid vesicles. J Biol Chem 1985; 260:1493.

Chang F-H, Bourne H: Dexamethasone in- creases adenylyl cyclase activity and ex- pression of the a-subunit of G, in GH3 cells. Endocrinology 1987: 121:1711.

TEM NovemheriDecemher 0 1989, Elsevier Science Publishing Co., Inc. 1043.2760/89/$3.50 15

Collu R, Bouvier C, Lagage G et al.: Selective deficiency of guanine nucleotide-binding protein G, in two dopamine-resistant pitu- itary tumors. Endocrinology 1988; 122: 1176.

Enjalbert A, Sladeczek F, Gilles G et al.: Angiotensin II and dopamine modulate both CAMP and inositol phosphate produc- tions in anterior pituitary cells. J Biol Chem 1986; 261:4071.

Gawler D, Milligan G, Spiegel A, Unson C, Houslay M: Abolition of the expression of inhibitory guanine nucleotide regulatory protein Gi activity in diabetes. Nature 1987; 327:229.

Gilman A: G proteins: transducers of recep- tor-generated signals. Annu Rev Biochem 1987; 56:515.

Glossmann H, Baukal A, Catt K: Angiotensin II receptors in bovine adrenal cortex. J Biol Chem 1974; 249:664.

Goldsmith P, Backlund PS Jr, Rossiter K et al.: Purification of Heterotrimeric GTP- binding proteins from brain: identification of a novel form of Go. Biochemistry 1988a; 27~7085.

Goldsmith P, Rossiter K, Carter A, et al.: Identification of the GTP-binding protein encoded by Gi3 complementary DNA. J Biol Chem 1988b; 263:6476.

Iyengar R, Birnbaumer L: Signal transduc- tion by G-proteins. ISI Atlas of Science: Pharmacology 1987; 1:2 13.

Kim D, Lewis DL, Graziadei, Neer EJ, Bar- Sagi D, Clapham DE: G-protein &sub- units activate the cardiac muscarinic K’- channel via phospholipase A*. Nature 1989; 337:557.

Lochrie MA, Simon MI: G protein multiplic- ity in eukaryotic signal transduction sys- tems. Biochemistry 1988; 27:4957.

Milligan G, Spiegel A, Unson C, Saggerson E: Chemically induced hypothyroidism pro- duces elevated amounts of the o! subunit of the inhibitory guanine nucleotide binding protein (G,) and the /3 subunit common to all G-proteins. Biochem J 1987; 247:223.

Munemura M, Agui T, Sibley D: Chronic estrogen treatment promotes a functional uncoupling of the Dz dopamine receptor in rat anterior pituitary gland. Endocrinol- ogy 1989; 124:346.

O’Dowd B, Lefkowitz R, Caron M: Structure of the adrenergic and related receptors. Annu Rev Neurosci 1989; 12167.

Roof DJ, Applebury ML, Sternweis PC: Rela- tionships within the family of GTP-bind- ing proteins isolated from bovine central nervous system. J Biol Chem 1985; 260:16242.

Rothenberg P, Kahn R: Insulin inhibits per- tussis toxin-catalyzed ADP-ribosylation of G-proteins. J Biol Chem 1988; 263:15546.

Senogles SE, Benovic JL, Amlaiky N et al.: The Dz-dopamine receptor of anterior pi- tuitary is functionally associated with a

pertussis toxin-sensitive guanine nucleo- tide binding protein. J Biol Chem 1987; 262:4860.

Sharp GWG, Marchand-Brustel Y, Yada T et al.: Galanin can inhibit insulin release by a mechanism other than membrane hyper- polarization or inhibition of adenylate cy- clase. J Biol Chem 1989; 264:7302.

Simonds WF, Goldsmith PK, Woodard CJ, Unson CG, Spiegel AM: Receptor and ef- fector interactions of G,: functional studies with antibodies to the (Y, carboxyl-ter- minal decapeptide. FEBS Lett 1989; 249:189.

Spiegel A, Carter A, Brann M, et al.: Signal transduction by guanine nuclcotide-bind- ing proteins. Ret Prog Horrn Res 1988: 44:337.

Vallar L, Spada A, Giannattasio G: Altered G, and adenylate cyclase activity in hu- man GH-secreting pituitary adenomas. Nature 1987; 330:566.

Zick Y, Sagi-Eisenberg R, Pines M, Gierschik P, Spiegel A: Multisite phosphorylation of the (Y subunit of transducin by the insulin receptor kinase and protein kinase C. Proc Nat1 Acad Sci USA 1986; 83:9294. TEM

Familial Multiple Endocrine Neoplasia Type 1 Mutation of a Tumor Suppressor Gene Stephen J. Marx

Familial multiple endocrine neoplasia type 1 (FMENl) is caused by mutation of a gene on the long arm of chromosome Il. Inactivation of both alleles at this locus in one cell is thought to cause loss of growth inhibition and development of a monoclonal tumor.

?? Definitions

Familial multiple endocrine neoplasia type 1 (FMENI) is an autosomal dominant syndrome with hyperfunc- tion of the parathyroids, the pancre- atic islets, and the anterior pitui- tary (Brandi et al. 1988). It should not be equated with all states that may be similarly described as multiple endocrine neoplasia type 1 (MENl). The term MEN1 is sometimes applied to sporadic cases with endocrine tu- mors in two or more of the organs affected in FMENl. Although FMENl is believed to reflect mutations at one lo- cus, MEN1 is highly heterogeneous in etiology. For example, it would include patients with pancreatic islet tumor- secreting growth hormone-releasing hormone (GHRH) (simultaneously

Stephen J. Marx is at the Mineral Metabo- lism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

causing a pituitary “tumor’‘-secreting growth hormone) and patients with a sporadic parathyroid adenoma plus a sporadic prolactinoma (two relatively common disorders that might occur concurrently).

The locus of the gene capable of transmitting susceptibility to the FMENl syndrome is the fmen1 locus. A normal (wild type [wt]) allele at this locus is fmenl”‘; an allele with a muta- tion that causes FMENl is fmenl*. A similar convention applies to loci of genes for other syndromes; thus, the familial adenomatous polyposis syn- drome (FAP) reflects mutation in the fap locus.

?? Clinical Features of FMENl

Possibility of Heterogeneous Etiologies

for FMENl

In the typical kindred with FMENI, 95% or more of members expressing the endocrinopathy show primary hyper-

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