The gene disrupted in Marinesco- Sjo ¨gren syndrome encodes SIL1, an HSPA5 cochaperone Anna-Kaisa Anttonen 1,2 , Ibrahim Mahjneh 3 , Riikka H Ha ¨ma ¨la ¨inen 1,2 , Clotilde Lagier-Tourenne 4 , Outi Kopra 5 , Laura Waris 1 , Mikko Anttonen 6 , Tarja Joensuu 1 , Hannu Kalimo 7 , Anders Paetau 7 , Lisbeth Tranebjaerg 8 , Denys Chaigne 9 , Michel Koenig 4 , Orvar Eeg-Olofsson 10 , Bjarne Udd 11 , Mirja Somer 12 , Hannu Somer 13 & Anna-Elina Lehesjoki 1 We identified the gene underlying Marinesco-Sjo ¨ gren syndrome, which is characterized by cerebellar ataxia, progressive myopathy and cataracts. We identified four disease-associated, predicted loss-of-function mutations in SIL1, which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5. These data, together with the similar spatial and temporal patterns of tissue expression of Sil1 and Hspa5, suggest that disturbed SIL1- HSPA5 interaction and protein folding is the primary pathology in Marinesco-Sjo ¨gren syndrome. Marinesco-Sjo ¨gren syndrome (MSS; OMIM 248800) is an autosomal recessive disorder that affects multiple tissues 1–3 . Cerebellar ataxia, due to cerebellar atrophy with Purkinje and granule cell loss 4 (Supple- mentary Fig. 1 online), is a hallmark of MSS. The myopathy is characterized by marked muscle replacement with fat and connective tissue, variation in fiber size, atrophic and necrotic myofibers, rimmed vacuoles and autophagic vacuoles with membranous whorls on electron microscopy 5,6 (Supplementary Fig. 1). Other cardinal fea- tures include bilateral cataracts, hypergonadotrophic hypogonadism and mild to severe mental retardation 3 . Skeletal abnormalities, short stature, dysarthria, strabismus and nystagmus are frequent findings. We confirmed linkage of the disease phenotype to the chromosome 5q31 locus 7 in a Finnish family, in which meiotic and historical recombinations defined a 3.52-Mb region with a shared haplo- type in Finnish individuals with MSS (Supplementary Fig. 2 and Supplementary Methods online). We observed the highest two-point lod score of 7.10 (at y ¼ 0.000) at marker D5S414 (data not shown). Haplotype analysis in two Swedish individuals with MSS (Supple- mentary Fig. 2) with Finnish paternal ancestors narrowed the region to 1.98 Mb between D5S500 and D5S2116. This excludes the gene SAR1B (also called SARA2; ref. 8), which was previously suggested as a candidate. We selected genes from the 1.98-Mb region for sequencing on the basis of tissue expression or predicted function. We identified a homozygous 4-nucleotide duplication (506_509dupAAGA) in exon 6 of SIL1 in all Finnish individuals with MSS, which is compatible with the predicted founder effect (Table 1, Fig. 1a and Supplementary Fig. 3 online). The Swedish individuals with MSS were compound heterozygous with respect to the 506_509dupAAGA mutation and a donor splice site mutation in intron 6 (645+2T-C; Table 1, Fig. 1a and Supplementary Fig. 3). We carried out RT-PCR analysis of SIL1 from lymphocyte RNA and found that the duplication mutant transcript was of the expected length whereas two shorter variants were expressed from the splice site mutated allele (Fig. 1a,b). In the shorter of these, which was expressed at higher levels, exon 6 was skipped (data not shown), predicting an in-frame deletion of Table 1 MSS-associated mutations in SIL1 Family Origin Nucleotide change Location Predicted amino acid change M1 Finland 506_509dupAAGA (homozygous) Exon 6 D170EfsX4 M4 Finland M5 Finland M6 Finland M12 Norway M2 Sweden 506_509dupAAGA Exon 6 D170EfsX4 645+2T-C (compound heterozygous) Intron 6 V186_Q215del A152_Q215del M11 Turkey 331C-T (homozygous) Exon 4 R111X M16 France 212dupA (homozygous) Exon 3 H71QfsX5 del, deletion; dup, duplication; fs, frameshift; X, stop. Received 17 June; accepted 31 August; published online 13 November 2005; doi:10.1038/ng1677 1 Folkha ¨ lsan Institute of Genetics and Neuroscience Center and 2 Department of Medical Genetics, University of Helsinki, PO Box 63, FI-00014 Helsinki, Finland. 3 Department of Neurology, Pietarsaari Hospital, PO Box 3, FI-68601 Pietarsaari, and Department of Neurology, University of Oulu, Oulu, Finland. 4 Institut de Ge ´ne ´ tique et de Biologie Mole ´ culaire et Cellulaire, CNRS/INSERM/Universite ´ Louis-Pasteur, 1 rue Laurent Fries, BP10142, FR-67404 Illkirch, France. 5 Neuroscience Center, University of Helsinki, PO Box 63, FI-00014 Helsinki, and Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland. 6 Children’s Hospital and Program for Developmental and Reproductive Biology, Biomedicum Helsinki, University of Helsinki, PO Box 63, FI-00014 Helsinki, Finland. 7 Department of Pathology, University of Helsinki and Helsinki University Central Hospital, PO Box 21, FI-00014 Helsinki, Finland. 8 Department of Medical Genetics, University Hospital of Tromsoe, Tromsoe, Norway; Department of Audiology, H:S Bispebjerg Hospital; and Wilhelm Johannsen Centre of Functional Genomics, Institute of Medical Biochemistry and Genetics IMBG, University of Copenhagen, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. 9 Neuropediatrie, Clinique Sainte Odile, 6 rue Simonis, FR-67100 Strasbourg, France. 10 Department of Women’s and Children’s Health / Pediatrics, Uppsala University, SE-751 85 Uppsala, Sweden. 11 Folkha ¨lsan Institute of Genetics, University of Helsinki, PO Box 63, FI-00014 Helsinki; Department of Neurology, Vaasa Central Hospital, Vaasa; and Department of Neurology, Tampere University Hospital, Tampere, Finland. 12 The Family Federation of Finland, PO Box 849, FI-00101 Helsinki, Finland. 13 Department of Neurology, University of Helsinki, PO Box 63, FI-00014 Helsinki, Finland. Correspondence should be addressed to A.-E.L. (anna-elina.lehesjoki@helsinki.fi). NATURE GENETICS VOLUME 37 [ NUMBER 12 [ DECEMBER 2005 1309 BRIEF COMMUNICATIONS © 2005 Nature Publishing Group http://www.nature.com/naturegenetics