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Urs-Schnyder-Lecture ESPD Dubrovnik Prof Dr. Dr. Judith Fischer

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Urs-Schnyder-Lecture ESPD Dubrovnik Prof Dr. Dr. Judith Fischer Urs-Schnyder-Lecture ESPD Dubrovnik 02.05.201 Prof Dr. Dr. Judith Fischer University Medical Center Freiburg Institute of Human Genetics Discovery of a gene encoding SLURP-1 in Mal de Meleda Positional cloning 1998 2000 2001 Folie 2 • Milestones • Methods Positional Cloning Homozygosity Mapping Next Generation Sequencing • My Gene identifications - highlights Folie 3 30 years ago… 1990 Department of Dermatology Prof. R. Happle Folie 4 1994 Lutetia = Paris EU-grant: Training and mobility 550km Genetics of psoriasis and genodermatoses Pr. L. Dubertret Dr. C. Blanchet-Bardon Dr. E. Bourrat Folie 5 1996 -1998 • Making tools available • Accelerate elucidation of diseases Genopole Evry • (Gene) Therapy / treatment Dr. J-F. Prud‘homme Dr. J. Weissenbach Dr. S. Saker (DNA bank) Folie 6 Positional Cloning – Reverse Genetics TOOLS MAPS COHORTS TECHNOLOGIES Physical maps DNA Patients Genotyping facilities YACs, BACs Families microsatellite-panels SNP-microarrays Genetic maps Linkage studies Bioinformatics, Statistics Microsatellites /SNPs Homozygosity Linkage (LOD scores) Human genome project mapping Association studies (p- HapMap (consanguineous) values) GWAS 1000 genome project Sequencing facilities Positional Cloning Using maps, cohorts and technologies 2001 First draft of Human genome sequence Gene1 Gene2 From: The general approach to positional cloning Folie 8 1998-2010 Genopole - Evry Gene identification • Positional cloning (< 2006) • Next Generation Sequencing NGS (> 2006) Whole Exome Sequencing Pr. M. Lathrop Pr. J. Weissenbach Folie 9 COHORTS DNA from > 1.000 families with genodermatoses CNG/Généthon: France Algeria Tunisia Morocco Turkey Italy Portugal UK Colombie Sub-Sahara Afrique Syria Spain Lebanon Geneskin EU Sweden Danmark Switzerland Italy Active Participation day and night in the Algerian desert 11 HOMOZYGOSITY MAPPING * I. A chromosomal region which 2 1 3 4 contains the segregating allele from a same ancestor is transmitted via both sides of II. * * the family Search for common 7 8 1 3 4 1 * homozygosity regions in * 5 6 affected children in consanguineous families III. 71 15 Strategy 3 times more powerful for localizing a gene * * * * Opportunity to localize genes IV. for very rare diseases 7 1 7 5 1 1 1 5 Discovery of a gene encoding SLURP-1 in Mal de Meleda Positional cloning 1998 2000 2001 Folie 13 Positional cloning of Mal de Meleda Family cohorts: Consanguineous families with Mal de Melda from Algeria Pr. B. Bouadjar Bouadjar B, Benmazouzia S, Prud'homme J, Cure S, Fischer J. Clinical and Genetic Studies of 3 Large, Consanguineous, Algerian Families With Mal de Meleda. Arch Dermatol. 2000;136(10):1247–1252. doi:10.1001/archderm.136.10.1247 Folie 14 Positional cloning of Mal de Meleda Family cohorts: Consanguineous families with Mal de Melda from Algeria Bouadjar B, Benmazouzia S, Prud'homme J, Cure S, Fischer J. Clinical and Genetic Studies of 3 Large, Consanguineous, Algerian Families With Mal de Meleda. Arch Dermatol. 2000;136(10):1247–1252. doi:10.1001/archderm.136.10.1247 Folie 15 Genetic linkage of Meleda disease to chromosome 8qter Fischer et al. (1998) Homozygosity mapping Fischer et al. (1998) Genetic linkage of Meleda disease to chromosome 8qter. Eur J Hum Genet Bouadjar et al. (2000) Clinical and Genetic Studies of 3 Large, Consanguineous, Algerian Families With Mal de Meleda Arch Dermatol. Folie 16 Genetic linkage of Meleda disease to chromosome 8qter Fischer et al. (1998) Folie 17 Mutations in the gene encoding SLURP-1 in Mal de Meleda Fischer et al. (2001) Hum Mol Genet Patient 1.9 1.11 1.6 2.12 3.19 6.12 7.10 9.5 10.10 11.4 12.9 14.3 16.3 17.3 18.15 4.17 5.9 8.10 13.3 15.6 19.3 Origin A A A A A A A A A A A C C C C A A A C C C Marker D8S1717 3 6 6 11 9 9 3 9 9 9 9 9 3 3 6 6 3 3 9 9 6 6 1 8 3 9 3 9 9 9 9 4 12 12 11 11 3 3 3 3 3 3 D8S1704 5 2 2 3 5 3 3 3 3 3 3 3 5 5 2 2 3 5 3 3 2 2 1 3 1 3 5 3 3 3 3 2 1 1 2 2 1 1 1 1 1 4 CNG001 7 3 3 4 4 5 11 5 7 7 5 5 2 2 3 3 5 2 5 5 3 3 4 6 4 6 1 5 6 6 2 5 6 6 4 4 4 4 4 4 4 8 D8S1727 3 4 - - 3 3 3 3 3 3 3 3 6 6 4 4 6 6 3 3 4 4 - - - - - - - - 8 8 3 3 - - 8 8 8 8 8 8 CNG002 4 2 2 1 2 2 2 2 4 4 2 2 2 2 2 2 2 2 2 2 2 2 2 3 1 1 3 2 1 1 2 2 2 2 3 3 2 2 2 2 2 3 CNG003 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 7 7 7 7 7 7 8 8 8 8 8 8 D8S1751 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 1 1 1 1 1 1 1 1 1 1 1 1 D8S1836 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 5 5 5 5 5 5 4 4 4 4 4 4 CNG004 7 7 7 7 8 11 5 5 9 9 11 11 6 6 7 7 6 6 11 11 4 4 6 6 6 6 6 6 6 6 9 9 7 9 9 9 6 6 6 6 6 6 CNG005 4 4 2 4 4 4 2 2 4 4 4 4 4 4 4 4 4 4 1 4 2 2 2 2 2 2 2 2 2 2 4 4 2 4 4 4 2 2 2 4 2 2 D8S2334 9 9 7 9 7 3 7 7 7 3 3 3 1 1 9 9 2 2 4 3 5 5 9 9 9 9 9 9 9 9 1 1 9 1 2 2 9 9 9 3 9 8 D8S1926 2 2 4 2 5 4 2 2 3 4 4 4 5 5 2 2 5 5 4 4 2 2 2 2 2 2 2 2 2 2 2 2 4 2 2 2 1 1 1 5 1 2 D8S1925 4 4 4 4 1 4 5 5 6 7 4 4 6 6 4 4 6 6 3 4 6 6 6 6 6 6 6 6 6 6 6 6 7 4 6 6 6 6 6 4 6 6 Mutation 82delT Altered Splicing C286T C28 32X 178+1g a R96X • 19 families, all patients with a homozygous haplotype on 8qter • Smallest segregating interval 1 cM (recombination events, loss of homozygosity) • Contained only 3 genes • Maximum LOD score 24.19 for marker CNG003 at θ = 0.0. • 3 different haplotpes – 3 different mutations in gene ARS (component B) • ARS (component B) : 3 exons, 103 amino acids • coding for SLURP-1 Folie 18 International cooperations 2002 - Dubrovnik, Zagreb, Evry, Lausanne, Edinburgh and Netherlands Folie 19 Marakchi et al., 2003 JID Large consanguineous pedigrees - Sfax Tunisia Folie 20 New mutations – 5 Haplotypes – Sfax Tunisia Marakchi et al., 2003 JID Folie 21 Slurping across the mare nostrum Commentary to Marrakchi et al. JID 2003, 120:351-355 Folie 22 Functional studies : group of Daniel Hohl Folie 23 Mapping/Localization Papillon-Lefevre-Syndrom 1997 1997 2001 1999, two different groups (Hart et al., Toomes et al.) reported first PLS to be due to mutations in the gene encoding cathepsin C, a lysosomal cysteine protease of the papain type also known as dipeptidyl aminopeptidase (CTSC and DPP1) Folie 24 Ichthyoses Autosomal Recessive Congenital Ichthyoses ARCIs Folie 25 Two new loci for autosomal recessive ichthyosis on Chromosomes 3p21 and 19p12-q12 and evidence for Further Genetic Heterogeneity (Fischer et al.) Positional cloning in 51 consanguineous families without TGM1 mutations 12 families linked to 2 new loci Chrom. Chrom. 3q21 19p12-19q12 2000 Folie 26 Locus on chrom. 3p21 : Syndromic ichthyosis Chanarin-Dorfman-Syndrom Neutral lipd storage syndrome with Ichthyosis NLSDI 2001 Folie 27 Jordan’s Chanarin- anomalies in Dorfman polynuclear granulocytes Syndrome NLSDI liver and muscle enzymes Two new mutations of the ABHD5 gene in a new adult case of Chanarin Dorfman syndrome: an uncommon lipid storage disease. Schleinitz et al 2005, Arch Dermatol. HES Muscle biopsy atrophic (Sudan black) muscle EM skin biopsy EM muscle HES skin biopsy with vacuoles in keratinocytes Some families with typical Jordans anomalies had NO MUTATIONS in CGI58/ABDH5 (?? *) Peripheral blood smear showing lipid vacuoles (arrows) in neutrophils (Jordans anomaly). Similar lipid deposition was also observed in hepatocyte nuclei. (Ciesek et al., 2006) Folie 29 *2007 PNPLA2 = ATGL = Adipos triglyceride lipase Folie 30 Mutations of ATGL/PNPLA2 in Neutral lipid storage disease with myopathy NLSDM Fischer et al., 2007 Mutations of ATGL/PNPLA2 in Neutral lipid storage disease with myopathy NLSDM Fischer et al., 2007 Comparaison of phenotypes, metabolic and biochemical defect between patients with NLSDM and CDS/NLSDI RT-PCR Accumulation of lipids in muscle and skin NLSDM Locus on 19p12-19q12 2006 Folie 34 Positional cloning of lamellar ichthyosis type 3 LI3 Fischer et al., 2000 6 consanguineous families Genome-wide scan with microsatellites →Search for common homozygosity regions 5.9 cM in affected children (Homozygosity mapping) Gene Localisation of LI3 on chromosome 19p21-q21 (Fischer et al 2000) Initial smallest common interval 5.9 cM 1cM ~1Mb 12 consanguineous families linked to chrom.
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