Inherited lipodystrophies are rare autosomal recessive and dominant disorders characterized by loss of adipose tissue. They also lead to severe insulin resistance, hyper-insulinemia, acanthosis nigricans, hypertriglyceridemia, diabetes mellitus, and fatty liver. An understanding of the molecular basis of these diseases will provide important insights into the development of body fat and the role it plays in modulating insulin and triglyceride levels. We localized partial lipodystrophy to chromosome 1q21 (Peters et al., 1998) following a genome-wide linkage scan with several multiply affected families. FPL was subsequently shown to be due to mutations in lamin A/C (Garg et al., 2002). This catalyzes acylation of lysophosphatidic acid to phosphatidic acid, a precursor for both triacylglycerol (TG) and phospholipid synthesis. We have also shown that AGPAT2 plays a critical role in adipocyte differentiation (Gale et al., 2006). Together with the observation that serum levels of leptin and adiponectin are reduced in individuals with CGL, our findings lend support to the hypothesis that CGL is primarily a disorder of adipocyte differentiation, and is not simply a defect in TG accumulation. A second form of CGL, Bernardinelli-Seip syndrome (OMIM #269700), maps to chromosome 11 and is due to mutations in BSCL2. The BSCL2 protein, termed seipin, is an integral membrane protein of the endoplasmic reticulum (ER) where it is found at lipid droplet junction. Heterozygous mutations in BSCL2 have also been reported in some of the autosomal dominant distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophies. These include Silver syndrome (OMIM #270685), distal hereditary motor neuropathy type V, variants of Charcot-Marie-Tooth disease type 2, and spastic paraplegia. Two independent mis-sense mutations in the consensus Asp-x-SIT glycosylation site in the N-terminal region of the protein, N88S and S90L are proposed to lead to altered glycosylation of seipin, aggregate formation, and neurodegeneration.

To investigate the function of seipin in lipodystrophy and dHMNs we are performing yeast-two-hybrid screens different segments of seipin as bait. We have identified several interactors whose interaction with seipin is abolished upon introduction of the A212P lipodystrophy mutation. The role of these interactions is being investigated in differentiating adipocytes (OP9 and 3T3-L1s). The effects of agonists and antagonists of interacting proteins upon adipocyte differentiation is also being investigated.

   Staining of differentiating adipocytes (OP9 cells) for seipin (green).
   Lipid droplets are shown in red (courtesy of Nathan Wolins).

Washington University School of Medicine, Department of Genetics, Division of Human Genetics
Last updated Sept. 2, 2009