A new laminopathy caused by an Arg133/Leu mutation in and the effects thereof on adipocyte differentiation and the transcriptome.

We report a new laminopathy that includes generalized lipoatrophy, insulin-resistant diabetes, micrognathia and biopsy-proven, focal segmental glomerulosclerosis in a female, caused by a de novo heterozygous mutation R133L in the lamin A/C gene (). We analysed the nuclear morphology and laminar distribution in 3T3-L1 pre-adipocytes overexpressing human wild-type lamin A/C ( WT) or lamin A/C with the R133L mutation ( R133L). We found the nuclear size was varied, nuclear membrane invagination or blebbing, and an irregular A-type lamin meshwork in cells overexpressing R133L.3T3-L1 pre-adipocyte differentiation into adipocytes was impaired in cells expressing R133L; contemporaneously, the expression levels of genes associated with adipose tissue self-renewal, including adipogenesis, angiogenesis, and extracellular matrix maintenance, were downregulated. Furthermore, the insulin-signalling pathway was inhibited in R133L adipocytes. Microarray gene expression profiling showed that the most prominent differences between 3T3-L1 cells expressing wild-type and R133L were in genes implicated in metabolic pathways, the cellular response to DNA damage and repair. We thus expand the clinical spectrum of laminopathy and conclude that the R133L mutation associated with lipodystrophic features and multisystem disorders likely impairs adipocyte renewal and disrupts the expression of genes implicated in the induction and repair of DNA damage.