Abstract
The most-severe form of congenital generalized lipodystrophy (CGL) is caused by mutations in BSCL2/seipin. Seipin is a homo-oligomeric integral membrane protein in the endoplasmic reticulum that concentrates at junctions with cytoplasmic lipid droplets (LDs). While null mutations in seipin are responsible for lipodystrophy, dominant mutations cause peripheral neuropathy and other nervous system pathologies. We first review the clinical aspects of CGL and the discovery of the responsible genetic loci. The structure of seipin, its normal isoforms, and mutations found in patients are then presented. While the function of seipin is not clear, seipin gene manipulation in yeast, flies, mice, and human cells has recently yielded a trove of information that suggests roles in lipid metabolism and LD assembly and maintenance. A model is presented that attempts to bridge these new data to understand the role of this fascinating protein.
Highlights
The most-severe form of congenital generalized lipodystrophy (CGL) is caused by mutations in BSCL2/ seipin
While results differ between humans and mice regarding seipin expression in adipose tissue, it is clear from studies in cultured cells from both organisms that seipin expression is connected to adipogenesis, the process of adipocyte differentiation that is driven by several factors in a complex temporal pathway [55, 56]
Adipogenesis can be divided into two major phases: 1) determination, during which mesenchymal stem cells are converted to preadipocytes, and 2) terminal differentation, in which preadipocytes induce the enzymes required for neutral lipid synthesis and storage
Summary
CGL was found to be inherited in an autosomal recessive manner and has since been observed in over 250 families around the world, with an estimated prevalence of 1 in 10 million [14]. After the mapping of the first locus, but shortly before the identification of AGPAT2, a second locus was discovered via linkage analysis on CGL families in Norway and Lebanon. This newly identified gene of unknown function was named BSCL2, or seipin [16], and is the subject of this review. Genetic studies indicate that more genetic loci exist for CGL, the four described here, AGPAT2, seipin, CAV1, and cavin-1, currently remain the only genes identified [2]
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