(mentions CMT 2 variants) Seipin/BSCL2-related motor neuron disease, seipinopath

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Rinsho Shinkeigaku. 2007 Jun;47(6):329-35.

Seipin/BSCL2-related motor neuron disease, seipinopathy is a novel

conformational disease associated with endoplasmic reticulum stress

Ito D, Suzuki N.

Department of Neurology, School of Medicine, Keio University.

In 2004, heterozygous mutations (N88S, S90L) in the Seipin/BSCL2

gene were identified in two autosomal dominant motor neuron

diseases, distal hereditary motor neuropathy type V (OMIM #182960)

and Silver syndrome (OMIM #270685). The Seipin/BSCL2 gene was

originally identified as a candidate gene for congenital generalized

lipodystrophy type 2 (CGL2) (OMIM #269700).

Individuals with homozygous null mutations in seipin have severe

lipoatrophy, insulin resistance, hypertriglyceridemia, and mental

retardation without any abnormality of the motor neurons. Recent

phenotype analyses of the N88S and S90L mutations have revealed a

wide spectrum of Seipin/BSCL2-related motor neuron diseases,

including Silver syndrome, distal hereditary motor neuropathy type

V, variants of Charcot-Marie-Tooth disease type 2, and spastic

paraplegia 17; therefore, these diseases should be

termed " seipinopathies " .

Seipin is a transmembrane protein that is localized in the

endoplasmic reticulum (ER). Interestingly, the N88S and S90L

mutations both disturb the N-glycosylation motif, suggesting that

improper glycosylation of seipin is closely associated with the

pathogenesis of motor neuron diseases. Our recent study demonstrated

that seipin is proteolytically cleaved into N and C-terminal

fragments and then polyubiquitinated. The N88S and S90L mutations

enhance ubiquitination and degradation by UPS, and N88S and S90L

mutants appear to be improperly folded, resulting in their

accumulation in the ER.

Furthermore, expression of mutant seipin in cultured cells activates

UPR stress and induces ER stress-mediated apoptosis. Our findings

suggest that seipin-related motor neuron diseases, seipinopathies

are novel conformational diseases, and we propose that the

pathological process of these diseases is tightly associated with ER

stress-mediated cell death.