Abstract
SIL1 (also called BAP) acts as a nucleotide exchange factor for the Hsp70 chaperone BiP (also called GRP78), which is a key regulator of the main functions of the endoplasmic reticulum. We found nine distinct mutations that would disrupt the SIL1 protein in individuals with Marinesco-Sjögren syndrome, an autosomal recessive cerebellar ataxia complicated by cataracts, developmental delay and myopathy. Identification of SIL1 mutations implicates Marinesco-Sjögren syndrome as a disease of endoplasmic reticulum dysfunction and suggests a role for this organelle in multisystem disorders.
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Acknowledgements
We thank the members of the families with MSS for their participation in this study; M.C. Walter for clinical work; and N.B. Romero and J.-P. Leroy for immunohistochemical and electron microscopy studies. J.S. was supported by the START program of the medical faculty of Aachen University of Technology and by the Doktor Robert Pfleger-Stiftung. Financial support of the Muscular Dystrophy Campaign to F.M. and M.B. is acknowledged. R.H., H.L., T.V. and J.W. are members of the German network on muscular dystrophies (MD-NET) funded by the German ministry of education and research (BMBF).
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Supplementary information
Supplementary Fig. 1
Expression analysis of the mouse orthologue Bap/Sil1 in tissues targeted by MSS. (PDF 45 kb)
Supplementary Fig. 2
Identification of BAP/SIL1 mutations. (PDF 344 kb)
Supplementary Fig. 3
Characterization of BAP/SIL1 splice site mutations. (PDF 312 kb)
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Senderek, J., Krieger, M., Stendel, C. et al. Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy. Nat Genet 37, 1312–1314 (2005). https://doi.org/10.1038/ng1678
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DOI: https://doi.org/10.1038/ng1678
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