Rare diseases - pioneers for common ones?

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1 Rare diseases - pioneers for common ones? ENGAGE Special Seminar Tribute to Leena Peltonen-Palotie Academician of Science Helsinki

2 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

3 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

4 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 Finnish Disease Heritage Leena s contribution CNA2, cornea plana congenita CNF, congenital nephrotic syndrome of Finnish type

5 Finnish Disease Heritage common interests 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

development visual failure epilepsy, myoclonus premature death intracellular

6 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

7 Classification of NCLs - classical Age of onset I 8-13 months INFANTILE NCL, INCL II 2-7 years LATE-INFANTILE NCL, LINCL III 4-10 years JUVENILE NCL, JNCL IV years ADULT NCL, ANCL

8 Classification of NCLs - modern Age of onset I At birth CONGENITAL NCL, CLN10; CTSD II 8-13 months INFANTILE NCL, INCL, CLN1; PPT1 LATE-INFANTILE NCL, LINCL, CLN2; TPP1 FINNISH VARIANT LATE- INFANTILE NCL, vlincl fin, CLN5 III 2-7 years VARIANT LATE- INFANTILE NCL, vlincl, CLN6 TURKISH VARIANT LATE- INFANTILE NCL, CLN7; MFSD8 CLN9-VARIANT NCL, CLN9 CLN8-VARIANT NCL, CLN8 IV 4-10 years JUVENILE NCL, JNCL, CLN3 NORTHERN EPILEPSY, EPMR, CLN8 V years ADULT NCL, ANCL, CLN4

10 Northern epilepsy Progressive epilepsy with mental retardation, EPMR autosomal recessive disorder; OMIM: described in 1994 in patients from Northern Finland in 2000 identified as a novel form of NCL: CLN8

Northern epilepsy CLN8 positional cloning of CLN8: encodes a novel TM protein of unknown function (Ranta et al. 1999) founder mutation in Finland: p.

11 Northern epilepsy CLN8 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) NH 2 COOH p. Gly237Arg

Turkish vlincl Age of onset: 2-7 years Epileptic seizures, motor impairment Mental regression, myoclonus, speech impairment, loss of vision and premature

12 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)

13 Mutations in CLN8 also underlie vlincl Ranta et al., 2004

14 Homozygosity mapping in 11 (mostly) consanguineous families Linkage peak on chromosome 4 Homozygous marker alleles over the peak region HLOD score peak 3.39 ~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

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

15 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 HA + Lamp1 Siintola et al., Am. J. Hum. Genet. 2007

16 MFSD8 mutations: a common cause of vlincl

17 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

18 Identification of candidate loci Homozygosity mapping in nuclear families Only shared homozygous regions between affected siblings considered Minimum homozygous segment length accepted: 1Mb

156 1681 8 33 241 16 80 732 17 16 165 N51

19 Homozygosity mapping Promising loci identified in families were evaluated for homozygosity in the sporadic patients Family Chromosome Genes Coding exons x N Total

20 Identification of CLN11 and CLN12 In collaboration with the Wellcome Trust Sanger Institute Aarno Palotie and Alison J Coffey NimbleGen sequencing capture protocol array Illumina sequencing for all coding exons Identification of two novel NCL genes

22 Intracellular localization of the NCL proteins Golgi apparatus CLN8 Lysosome ER CLN6 CLN8 CLN3 CLN5 CTSD (CLN10) CLN3 TPP1 (CLN2) PPT1 (CLN1) Endosomes MFSD8 (CLN7)

23 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?

24 Lehesjoki group (NCL projects) Acknowledgements Outi Kopra, PhD Susanna Ranta, MD, PhD Liina Lonka, PhD Eija Siintola, PhD Mervi Kuronen, MSc Maria Kousi, MSc 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 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 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

25 Thank you Leena!!

FINNISH DISEASE HERITAGE

1 Faculty of Biochemistry and Molecular Medicine: Molecular, cell biological and genetic aspects of diseases FINNISH DISEASE HERITAGE Sanna Karppinen 15.11.2017 Marjo Kestilä & Minna Männikkö, Heli Ruotsalainen