Title : Heterozygous missense mutations in
BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome
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 limbs
- 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 limbs
- 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 (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