Windpassinger, C and Auer-Grumbach, M and Irobi, J and Patel, H and Petek, E and Horl, G and Malli, R and Reed, JA and Dierick, I and Verpoorten, N and Warner, TT and Proukakis, C and Van den Bergh, P and Verellen, C and Van Maldergem, L and Merlini, L and De Jonghe, P and Timmerman, V and Crosby, AH and Wagner, K (2004) Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. NAT GENET , 36 (3) 271 - 276. 10.1038/ng1313.
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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 limbs(1). Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands and occasionally also the lower limbs(2,3). 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 lipodystrophy 5 (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.
|Title:||Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome|
|Keywords:||SPINAL MUSCULAR-ATROPHY, CHROMOSOME 11Q12-Q14, AGGRESOME FORMATION, SPASTIC PARAPLEGIA, HETEROGENEITY|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Clinical Neuroscience|
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Molecular Neuroscience
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