Abstract
Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (OMIM #182960) is a heterogeneous group of disorders characterized by an almost exclusive degeneration of motor nerve fibers, predominantly in the distal part of the limbs1. Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12–q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands and occasionally also the lower limbs2,3. Silver syndrome and most forms of dHMN are autosomal dominantly inherited with incomplete penetrance and a broad variability in clinical expression. A genome-wide scan in an Austrian family with dHMN-V (ref. 4) showed linkage to the locus SPG17, which was confirmed in 16 additional families with a phenotype characteristic of dHMN or Silver syndrome. After refining the critical region to 1 Mb, we sequenced the gene Berardinelli-Seip congenital lipodystrophy (BSCL2) and identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L. Null mutations in BSCL2, which encodes the protein seipin, were previously shown to be associated with autosomal recessive Berardinelli-Seip congenital lipodystrophy5 (OMIM #269700). We show that seipin is an integral membrane protein of the endoplasmic reticulum (ER). The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration.
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Acknowledgements
We thank the affected individuals and their family members for their participation; H. Offenbacher, A. Irmler and R. Fischer for their contribution in recruiting the families; A. Krenn and A. Legenstein for technical assistance; and W. Graier and E. Steyrer for critical discussion of the manuscript. This research project was supported by the Muscular Dystrophy Association, USA; the Fonds zur Förderung der wissenschaftlichen Forschung, Austria; the Tom-Wahlig-Stiftung Jena, Germany; the Fachabteilung 6A - Wissenschaft und Forschung of the Land Steiermark; the Birth Defects Foundation, UK; the University of Antwerp, the Fund for Scientific Research - Flanders; the Medical Foundation Queen Elisabeth; the Association Belge contre les Maladies Neuromusculaires, and the Interuniversity Attraction Poles programme of the Belgian Federal Science Policy Office, Belgium. I.D. and N.V. are supported by Ph.D. fellowships of the Institute for Science and Technology, Belgium. The Institutes of Medical Biology and Human Genetics and of Medical Biochemistry & Medical Molecular Biology are members of the Institutes of Basic Medical Sciences at the University of Graz and were supported by the infrastructure program of the Austrian ministry of education, science and culture.
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Windpassinger, C., Auer-Grumbach, M., Irobi, J. et al. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet 36, 271–276 (2004). https://doi.org/10.1038/ng1313
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DOI: https://doi.org/10.1038/ng1313
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