Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy

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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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Figure 1: Clinical findings, haplotype analysis, map of the MSS region of interest, organization of SIL1 and consequences of in-frame exon deletions.


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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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Correspondence to Jan Senderek.

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The authors declare no competing financial interests.

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)

Supplementary Methods (PDF 32 kb)

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