Mutations in the LMNA gene that encodes nuclear lamins A and C have been shown to cause Dunnigan-type partial lipodystrophy, an autosomal dominant inherited disease characterized by regional fat loss and insulin resistance. This finding implicates lamins A and C, intermediate filament proteins of the nuclear envelope, as part of a novel pathway involved in the control of body fat distribution. Our hypothesis is that dominantly acting mutations in lamins A and C interfere with this pathway that regulates fat cell differentiation or survival. The goal of this exploratory research project is to determine if mutant lamin A from patients with Dunnigan-type partial lipodystrophy blocks adipocyte differentiation or decreases adipocyte survival in vitro and in vitro.
In Specific Aim 1, we will study 3T3-L1 pre-adipocyte cell lines that express wild-type lamin A with missense mutations found in patients with Dunnigan-type partial lipodystrophy. We will examine these cells and determine if the mutant lamin A blocks their in vitro differentiation into adipocytes or decreases their survival.
In Specific Aim 2, we will create transgenic mouse lines that express wild-type and mutant lamin A under control of an Ap2 adipocyte-active promoter. Adipocyte cell distribution will be assessed in the transgenic mice, both at young and older ages as, in humans, fat loss in Dunnigan-type partial lipodystrophy occurs after the onset of puberty. The work in the exploratory project will prove or disprove the hypothesis that nuclear lamin A functions in fat cell development or survival. Confirmation of this hypothesis will have implications for the identification of new cellular targets to treat human obesity and diabetes mellitus.
| Boguslavsky, Revekka L; Stewart, Colin L; Worman, Howard J (2006) Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 15:653-63 |
| Worman, Howard J (2005) Inner nuclear membrane and signal transduction. J Cell Biochem 96:1185-92 |
| Muchir, Antoine; Worman, Howard J (2004) The nuclear envelope and human disease. Physiology (Bethesda) 19:309-14 |
