Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.
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.
Windpassinger
Christian
C
Institute of Medical Biology and Human Genetics, Medical University Graz, Harrachgasse 21/8, A-8010 Graz, Austria.
Auer-Grumbach
Michaela
M
Irobi
Joy
J
Patel
Heema
H
Petek
Erwin
E
Hörl
Gerd
G
Malli
Roland
R
Reed
Johanna A
JA
Dierick
Ines
I
Verpoorten
Nathalie
N
Warner
Thomas T
TT
Proukakis
Christos
C
Van den Bergh
Peter
P
Verellen
Christine
C
Van Maldergem
Lionel
L
Merlini
Luciano
L
De Jonghe
Peter
P
Timmerman
Vincent
V
Crosby
Andrew H
AH
Wagner
Klaus
K
D001842:Bone and Bones / Q000002:abnormalities; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics*; D018740:Genetic Heterogeneity; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics*; D006801:Humans; D009046:Motor Neurons / Q000473:pathology; D020125:Mutation, Missense; D020335:Paraparesis / Q000235:genetics; D013577:Syndrome
C432679:BSCL2 protein, human; D044388:GTP-Binding Protein gamma Subunits