Identification of genetic modifiers modulating the diseases severity of LMNA-CMD
Muscular Dystrophy UK
INSERM
LMNA gene mutations are responsible for a wide spectrum of disorders, the majority of which affecting striated muscles with dilated cardiomyopathy. They may be associated with variable severity of muscular dystrophy, i.e. LGMD1B (mild/late muscle phenotype), EDMD (strong/young muscle phenotype) and LMNA-CMD (severe/congenital onset of muscle phenotype). Analyses of clinical and genetic data collected in the UMD-LMNA mutation database (www.umd.be/LMNA/) that we set up led to the identification of few LMNA hot-spot mutations associated with different severity of the disease and highlighted a vast genetic and clinical heterogeneity among carriers of a similar LMNA mutation. Although digenism could explain part of this heterogeneity, involvement of modifier genes has also been suggested.  LMNA encodes for 2 protein isoforms: lamin A and lamin C. They are intermediate filaments of the nucleus, mainly localized underneath the inner nuclear membrane but also dispersed in the nucleoplasm at low level. Analyses of EDMD and LMNA-CMD patient and mouse cells have revealed an increase in the nucleoplasmic lamin A/C specifically in LMNA-CMD. In the current project, we aim at identifying such modifiers using whole genome sequencing and/or RNA-sequencing in a large French family presenting with either isolated cardiac disease or EDMD with variable age at onset of myopathic symptoms (AOMS) (aim 1) and in a cohort of patients harbouring the same EDMD hot-spot mutation presenting with more severe, congenital phenotype than usually observed (aim 2). Finally, aim 3 will functionally validate the different variants that would be identified in aims 1 and 2 using patient cells.
2.1 Biological and endogenous factors