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.