AB091. Analysis of LA2 as a functional candidate gene for Emery Dreifuss muscular dystrophy and dilated cardiomyopathy

Abstract: Laminopathies are rare genetic disorders caused by mutations in genes encoding lamins or lamin-interacting proteins. LMNA, EDM and to a lower measure the Nesprin genes have been associated with Emery Dreifuss muscular dystrophy (EDMD), characterized by contractures of the Achilles tendons, progressive skeletal muscle weakness and heart rhythm disturbances leading to dilated cardiomyopathy (DCM) and sudden cardiac death. Since ~60% EDMD patients are not associated to known genes, we used a functional candidate-gene approach to identify additional EDMD disease genes. Based on reported interactions of lamina associated polypeptide 2 (LAP2) with nucleoplasmic lamin A/C and the association of the LAP2alpha isoform to DCM (Matthew R.G Taylor et al. 2005), 111 EDMD and 87 DCM patients were investigated for DNA variations in LAP (encoding six LAP2 isoforms) using heteroduplex analysis and direct sequencing. Among ten variations found, four changes—p.P426L (c.1481C>T) in LAP2alpha, p.D271E (c.1054T>G) in LAP2beta, and p.V423L (c.1058G>C) and p.M381I (c.1387 G>A) in LAP2gamma—were unique for EDMD patients, but segregation analysis indicated only p.P426L LAP2alpha as a mutation potentially associated to EDMD. P426L-LAP2 alpha localized to the nucleoplasm in skin fibroblasts, like wild-type protein and did not affect the loalization of lamin A. However, in mutant fibroblast cultures phosphorylated retinoblastoma protein (Rb) levels were reduced compared to wild-type cultures, sugesting that the mutated protein may affect cell cycle progression in agreement with previous studies implicating LAP2alpha-lamin A in Rb-mediated cell cycle control. The present study shows that LAP2alpha mutations might add to the pathology of EDMD in ~1% of EDMD patients.

Keywords: Laminopathies; LAP2alpha; mutations; Emery Dreifuss muscular dystrophy (EDMD)