ARSACS, a spastic ataxia common in northeastern Québec, is caused by mutations in a new gene encoding an 11.5-kb ORF

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS or SACS) is an early onset neurodegenerative disease with high prevalence (carrier frequency 1/22) in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region of Quebec. We previously mapped the gene responsible for ARSACS to chromosome 13q11 and identified two ancestral haplotypes. Here we report the cloning of this gene, SACS, which encodes the protein sacsin. The ORF of SACS is 11,487 bp and is encoded by a single gigantic exon spanning 12,794 bp. This exon is the largest to be identified in any vertebrate organism. The ORF is conserved in human and mouse. The putative protein contains three large segments with sequence similarity to each other and to the predicted protein of an Arabidopsis thaliana ORF. The presence of heat-shock domains suggests a function for sacsin in chaperone-mediated protein folding. SACS is expressed in a variety of tissues, including the central nervous system. We identified two SACSmutations in ARSACS families that lead to protein truncation, consistent with haplotype analysis.

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Figure 1: The extent of linkage disequilibrium for the ARSACS region compared with the diastrophic dysplasia (DTD) region.
Figure 2: Structure and organization of SACS.
Figure 3: Sequence analysis and identification of SACS mutations in ARSACS patients.
Figure 4: Northern-blot analysis of SACSmRNA.
Figure 5: Darkfield autoradiograph of tissues hybridized to probes complementary to human SACS and mouse Sacs mRNAs (a,c,e, g) and to sense probes (b,d,f,h).
Figure 6: Deduced amino acid sequence and structure of sacsin.

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Acknowledgements

We thank the patients and families for participation; J. Graham, E.A. Thompson, B.F.F. Ouellette, J.D. Rioux, T.M. Fujiwara, P. Lee, M. Shapiro and C.M. Neville for helpful discussions; E.A. Thompson for a computer program for the coalescent method; E. Heyer and H. Vézina for demographic information; J. Ma for assistance in the creation of M13 subclone libraries; F. Gosselin and C. Prevost for sample collection and pedigree information; C. Goguen for administrative assistance; and C. Bieri for computer expertise. This work was supported by grants from the Medical Research Council of Canada (MRC; to A.R., S.B.M., K.M. and T.J.H.), the Muscular Dystrophy Association of Canada (to A.R., S.B.M. and T.J.H.), the March of Dimes (to A.R. and S.B.M.), the National Ataxia Foundation (to A.R. and S.B.M.), l'Institut Interuniversitaire de Recherches sur les Populations (to J.M., T.J.H. and K.M.), the Canadian Genetic Diseases Network (Networks of Centres of Excellence Program (NCE); to T.J.H. and K.M.), the Mathematics of Information Technology and Complex Systems (NCE; to K.M.), the Swedish Medical Research Council (to M.S.) and a research contract from Bristol-Myers Squibb, Millennium Pharmaceuticals Inc. and Affymetrix (to E.S.L. and T.J.H.). T.J.H. is a recipient of a Clinician Scientist Award from the MRC.

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Correspondence to Thomas J. Hudson or Andrea Richter.

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Engert, J., Bérubé, P., Mercier, J. et al. ARSACS, a spastic ataxia common in northeastern Québec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nat Genet 24, 120–125 (2000). https://doi.org/10.1038/72769

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