Abstract
The past decade has seen great advances in unraveling the biological basis of hereditary ataxias. Molecular studies of spinocerebellar ataxias (SCA) have extended our understanding of dominant ataxias1. Causative genes have been identified for a few autosomal recessive ataxias: Friedreich's ataxia2, ataxia with vitamin E deficiency3, ataxia telangiectasia4, recessive spastic ataxia of Charlevoix-Saguenay5 and ataxia with oculomotor apraxia type 1 (refs. 6,7) and type 2 (ref. 8). Nonetheless, genes remain unidentified for most recessive ataxias. Additionally, pure cerebellar ataxias, which represent up to 20% of all ataxias, remain poorly studied with only two causative dominant genes being described: CACNA1A (ref. 9) and SPTBN2 (ref. 10). Here, we report a newly discovered form of recessive ataxia in a French-Canadian cohort and show that SYNE1 mutations are causative in all of our kindreds, making SYNE1 the first identified gene responsible for a recessively inherited pure cerebellar ataxia.
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Acknowledgements
The authors thank all family members for their entire cooperation. The authors also thank D. Verlaan and P. Cossette for helpful discussion on the linkage study, C. Gaspar for careful review of this manuscript, P. Hince for technical assistance with the immunohistological experiments, F. Gosselin for collecting blood from affected individuals and N. Chrestian for data acquisition and management. We are grateful for the support of T. Hudson from the McGill University Genome Québec Innovation Centre. We thank P. Greengard for antibody to synapsin. F.G.L., N.D. and G.A.R. are supported by the Canadian Institutes of Health Research (CIHR). This project was funded by the Canadian Genetic Diseases Network (CGDN), by the US National Ataxia Foundation and by a grant from the US National Institutes of Health to J.R.S.
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F.G.-L. generated the data, conducted the data analysis, wrote the manuscript and led the project; N.D. conducted neurological evaluation of individuals with ARCA1, described the ARCA1 phenotype and reviewed the manuscript; P.D. participated in the data analysis and review of the manuscript; M.A.F. conducted and analyzed in vitro neuromuscular junction experiments and reviewed the manuscript; S.L. provided technical assistance in generating data; S.V. participated in the neurological evaluation of individuals with ARCA1; J.R.S. supervised and analyzed the in vitro neuromuscular junction experiments and reviewed the manuscript; J.-P.B. conducted neurological evaluation of individuals with ARCA1, described the ARCA1 phenotype and reviewed the manuscript; G.A.R. conducted neurological evaluation of individuals with ARCA1, described the ARCA1 phenotype, participated in the data analysis, reviewed the manuscript and supervised the project.
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Supplementary information
Supplementary Fig. 1
Magnetic resonance imaging of affected subjects in sagittal T1 and axial T2 showing marked diffuse cerebellar atrophy with no cortical or brainstem atrophy. (PDF 148 kb)
Supplementary Fig. 2
Pedigrees with autosomal recessive cerebellar ataxia type 1 used for the genome-wide scan analysis. (PDF 52 kb)
Supplementary Table 1
Genome-wide linkage results. (PDF 49 kb)
Supplementary Table 2
Details, location, and genomic context of each variant detected. (PDF 14 kb)
Supplementary Table 3
PCR primer pair sequences. (PDF 43 kb)
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Gros-Louis, F., Dupré, N., Dion, P. et al. Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia. Nat Genet 39, 80–85 (2007). https://doi.org/10.1038/ng1927
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DOI: https://doi.org/10.1038/ng1927
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