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!!