Post on 29-Sep-2020
transcript
Rare diseases - pioneers for common ones?
ENGAGE Special Seminar
Tribute to Leena Peltonen-Palotie Academician of Science
Helsinki 31.5. 2010
“Finnish disease heritage”
• a group of rare hereditary diseases overrepresented in Finland • rarity of many hereditary disorders relatively common elsewhere
• founder effect • genetic drift • national isolation • regional isolation
GRACILE,growth ret., iron, lact acidosis LAAHD, lethal arthogryposis
FSH-RO, gonadal dysgenesis EPMR, northern epilepsy (CLN8) PEHO, infantile cerebellooptic atrophy TMD, tibial muscular dystrophy, dominant RAPADILINO, rapadilino syndrome LCCS, lethal congenital contracture syndrome IOSCA, infantile onset spinocerebellar ataxia CHS, Cohen syndrome vLINCL, variant late infantile ceroid lipofuscinosis (CLN5) HLS, hydrolethalus syndrome SALLA, sialic acid storage disease MKS, Meckel syndrome MEB, muscle eye brain disease CHM, choroideremia, X-recessive INCL, infantile neuronal ceroid lipofuscinosis (CLN1) HOGA, gyrate atrophy of the choroid and retina DTD, diastrophic dysplasia JNCL, juvenile neuronal ceroid lipofuscinosis (CLN3) CHH, cartilage-hair dysplasia MUL, mulibrey nanism FAF, familial amyloidosis of Finnish type, dominant PLO-SL, polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy USH3, Usher syndrome type III AGU, aspartylglucosaminuria CLD, congenital lactase deficiency NKH, nonketotic hyperglycinemia LPI, lysinuric protein intolerance CCD, congenital chloride diarrhea APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy RS, juvenile retinoschisis, X-recessive EPM1, progressive myoclonus epilepsy of Unverricht-Lundborg type SMB12, selective intestinal malabsorption of vitamin-B12 CNA2, cornea plana congenita CNF, congenital nephrotic syndrome of Finnish type 56... 58... 60... 62... 64... 66... 68... 70... 72... 74... 76... 78... 80... 82... 84 ...86... 88... 90... 92... 94... 96... 98
GRACILE,growth ret., iron, lact acidosis LAAHD, lethal arthogryposis
FSH-RO, gonadal dysgenesis EPMR, northern epilepsy (CLN8) PEHO, infantile cerebellooptic atrophy TMD, tibial muscular dystrophy, dominant RAPADILINO, rapadilino syndrome LCCS, lethal congenital contracture syndrome IOSCA, infantile onset spinocerebellar ataxia CHS, Cohen syndrome vLINCL, variant late infantile ceroid lipofuscinosis (CLN5) HLS, hydrolethalus syndrome SALLA, sialic acid storage disease MKS, Meckel syndrome MEB, muscle eye brain disease CHM, choroideremia, X-recessive INCL, infantile neuronal ceroid lipofuscinosis (CLN1) HOGA, gyrate atrophy of the choroid and retina DTD, diastrophic dysplasia JNCL, juvenile neuronal ceroid lipofuscinosis (CLN3) CHH, cartilage-hair dysplasia MUL, mulibrey nanism FAF, familial amyloidosis of Finnish type, dominant PLO-SL, polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy USH3, Usher syndrome type III AGU, aspartylglucosaminuria CLD, congenital lactase deficiency NKH, nonketotic hyperglycinemia LPI, lysinuric protein intolerance CCD, congenital chloride diarrhea APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy RS, juvenile retinoschisis, X-recessive EPM1, progressive myoclonus epilepsy of Unverricht-Lundborg type SMB12, selective intestinal malabsorption of vitamin-B12 CNA2, cornea plana congenita CNF, congenital nephrotic syndrome of Finnish type 56... 58... 60... 62... 64... 66... 68... 70... 72...
Finnish Disease Heritage – Leena’s contribution
74... 76... 78... 80... 82... 84 ...86... 88... 90... 92... 94... 96... 98
GRACILE,growth ret., iron, lact acidosis LAAHD, lethal arthogryposis
FSH-RO, gonadal dysgenesis EPMR, northern epilepsy (CLN8) PEHO, infantile cerebellooptic atrophy TMD, tibial muscular dystrophy, dominant RAPADILINO, rapadilino syndrome LCCS, lethal congenital contracture syndrome IOSCA, infantile onset spinocerebellar ataxia CHS, Cohen syndrome vLINCL, variant late infantile ceroid lipofuscinosis (CLN5) HLS, hydrolethalus syndrome SALLA, sialic acid storage disease MKS, Meckel syndrome MEB, muscle eye brain disease CHM, choroideremia, X-recessive
Finnish Disease Heritage – common interests
74... 76... 78... 80... 82... 84 ...86... 88... 90... 92... 94... 96... 98
INCL, infantile neuronal ceroid lipofuscinosis (CLN1) HOGA, gyrate atrophy of the choroid and retina DTD, diastrophic dysplasia JNCL, juvenile neuronal ceroid lipofuscinosis (CLN3) CHH, cartilage-hair dysplasia MUL, mulibrey nanism FAF, familial amyloidosis of Finnish type, dominant PLO-SL, polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy USH3, Usher syndrome type III AGU, aspartylglucosaminuria CLD, congenital lactase deficiency NKH, nonketotic hyperglycinemia LPI, lysinuric protein intolerance CCD, congenital chloride diarrhea APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy RS, juvenile retinoschisis, X-recessive EPM1, progressive myoclonus epilepsy of Unverricht-Lundborg type SMB12, selective intestinal malabsorption of vitamin-B12 CNA2, cornea plana congenita CNF, congenital nephrotic syndrome of Finnish type 56... 58... 60... 62... 64... 66... 68... 70... 72...
Neuronal ceroid lipofuscinoses (NCLs)
• most common neurodegenerative disorders of children • autosomal recessive inheritance • variable age of onset • failure of psychomotor development • visual failure • epilepsy, myoclonus • premature death • intracellular accumulation of autofluorescent lipopigment
Storage material in CLN8 neurons;
Courtesy of Matti Haltia
Classification of NCLs - classical
INFANTILE NCL, INCL
Age of onset
8-13 months
LATE-INFANTILE NCL, LINCL 2-7 years
JUVENILE NCL, JNCL
ADULT NCL, ANCL
4-10 years
11-50 years
I
II
III
IV
Classification of NCLs - modern
INFANTILE NCL, INCL, CLN1; PPT1
Age of onset
8-13 months
LATE-INFANTILE NCL, LINCL, CLN2; TPP1
2-7 years
JUVENILE NCL, JNCL, CLN3
ADULT NCL, ANCL, CLN4
4-10 years
11-50 years
FINNISH VARIANT LATE- INFANTILE NCL, vLINCLfin, CLN5
TURKISH VARIANT LATE- INFANTILE NCL, CLN7; MFSD8
CLN8-VARIANT NCL, CLN8
CONGENITAL NCL, CLN10; CTSD At birth
VARIANT LATE- INFANTILE NCL, vLINCL, CLN6
I
II
III
IV
V
CLN9-VARIANT NCL, CLN9
NORTHERN EPILEPSY, EPMR, CLN8
Northern epilepsy Progressive epilepsy with mental retardation, EPMR
• autosomal recessive disorder; OMIM: 600143 • described in 1994 in patients from Northern Finland • in 2000 identified as a novel form of NCL: CLN8
Northern epilepsy CLN8
NH2
COOH
p. Gly237Arg
• positional cloning of CLN8: encodes a novel TM protein of unknown function (Ranta et al. 1999)
• founder mutation in Finland: p.Arg24Gly
• naturally occurring mouse model: mnd (Ranta et al. 1999)
• CLN8 is an ER resident protein (Lonka et al. 2000)
• CLN8 a member of a novel family of proteins with lipid-sensing domains (Winter and Ponting 2002)
Turkish vLINCL
• Age of onset: 2-7 years
• Epileptic seizures, motor impairment
• Mental regression, myoclonus, speech impairment, loss of vision and premature death
• Rapid progression
• EM: condensed FPP±CL in skin or lymphocytes
• Turkish vLINCL was initially considered a distinct clinical and genetic entity (CLN7)
Mutations in CLN8 also underlie vLINCL
Ranta et al., 2004
Homozygosity mapping in 11 (mostly) consanguineous families
• ~20 Mb homozygous region contains at least 90 known or putative genes • Positional candidate genes chosen based on the known or predicted functions of the
encoded proteins
HLOD score peak 3.39
Linkage peak on chromosome 4 Homozygous marker alleles over the peak region
CLN7 encodes the major facilitator superfamily domain containing 8 (MFSD8) protein
• six homozygous mutations in six families
• a 518 amino acid protein, Mw ~58 kDa • 12 predicted transmembrane domains • evolutionary conserved • putative lysosomal transporter • unknown substrate specificity and
cellular function
Siintola et al., Am. J. Hum. Genet. 2007
HA + Lamp1
MFSD8 mutations: a common cause of vLINCL
Identification of novel NCL genes
69 Turkish patients excluded from all known human NCL loci
5 nuclear families and 19 sporadic patients
Illumina human 610-quad dna analysis beadchip
Illumina’s Beadstudio-suite and PLINK used to identify candidate loci
Identification of candidate loci
• Homozygosity mapping in nuclear families
• Only shared homozygous regions between affected siblings considered
• Minimum homozygous segment length accepted: 1Mb
Homozygosity mapping
Promising loci identified in families were evaluated for homozygosity in the sporadic patients
Family Chromosome Genes Coding exons
x 3 156 1681 8 33 241 16 80 732 17 16 165
N51 1 79 713 1 17 187 3 85 1077 16 18 243
Total 484 5039
Identification of “CLN11 and CLN12”
NimbleGen sequencing capture protocol array
Illumina sequencing for all coding exons
In collaboration with the Wellcome Trust Sanger Institute Aarno Palotie and Alison J Coffey
Identification of two novel NCL genes
Golgiapparatus
Lysosome
ER
CLN8
CLN8
PPT1(CLN1)
TPP1(CLN2)
CTSD(CLN10)
CLN3
CLN5
CLN6
MFSD8(CLN7)
Intracellular localization of the NCL proteins
Endosomes
CLN3
Conclusions
• rare diseases are pioneers for the common ones!
• NCLs
• highly heterogeneous
• eight genes and still counting
• a model for common disorders?
• utilization of founder populations and inbred families in
Mendelian diseases - relevance for multifactorial ones?
Acknowledgements
Meral Topcu, Ankara, Turkey Callum Wilson, Auckland, New Zealand Lenka Dvorakova and Milan Elleder, Prague, Czech Reb. Sara Mole, London, UK Berge Minassian, Toronto Canada
Jonathan Cooper, London UK
Lehesjoki group (NCL projects)
Outi Kopra, PhD
Susanna Ranta, MD, PhD Liina Lonka, PhD Eija Siintola, PhD
Mervi Kuronen, MSc Maria Kousi, MSc
Teija Toivonen, reseach assistant
Folkhälsan Institute of Genetics and Neuroscience Center, University of Helsinki, Finland
FUNDING: Folkhälsan Research Foundation Academy of Finland University of Helsinki European Commission
Aarno Palotie, Sanger Center and FIMM Alison J Coffey, Sanger Center
Anu Jalanko, THL and FIMM Aija Kyttälä, THL and FIMM Jaana Tyynelä, University of Helsinki
Leonard Khirug, University of Helsinki
Thank you Leena!!