[Seipin/BSCL2-related motor neuron disease: Seipinopathy is a novel conformational disease associated with endoplasmic reticulum stress].

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.