Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and alpha-helical rod domains of the lamin A/C gene

Abstract

Purpose Mutations in different domains of the LMNA (lamin A/C) gene encoding nuclear envelope proteins lamin A and lamin C cause familial partial lipodystrophy (Dunnigan variety), dilated cardiomyopathy, and autosomal dominant forms of Emery-Dreifuss and limb-girdle muscular dystrophies. The objective of this study was to evaluate LMNA variants in two families with familial partial lipodystrophy (Dunnigan variety) who also had cardiac conduction system defects and other manifestations related to cardiomyopathy. Methods We performed mutational analysis of the lamin A/C gene in affected and unaffected subjects by deoxyribonucleic acid sequencing of the exons. Results Two novel missense mutations were identified in exon 1 of the lamin A/C gene. One mutation, R28W (CGG→TGG), affected the amino-terminal head domain, and the other, R62G (CGC→GGC), affected the α-helical rod domain. Affected subjects from both families had an increased prevalence of cardiac manifestations, such as atrioventricular conduction defects, atrial fibrillation, and heart failure due to ventricular dilatation, as well as pacemaker implantation. The proband from one of the families also had proximal muscle weakness. Conclusion Novel genetic defects in the LMNA gene in two families with the Dunnigan variety of familial partial lipodystrophy, cardiac conduction system defects, and other manifestations related to cardiomyopathy suggest the occurrence of a multisystem dystrophy syndrome due to LMNA mutations.