Mutation analysis of the lamin A/C gene (LMNA) among patients with different cardiomuscular phenotypes

Laminopathies represent a heterogeneous group of genetic disorders characterised by mutations in the LMNA gene, which encodes two lamins, A and C, by alternative splicing of the primary transcript.1 Lamins belong to the intermediate filament multigene family and form the nuclear lamina, a mesh-like structure adjacent to the nucleoplasmic side of the inner nuclear membrane.2 They interact with emerin, the proteins encoded by the gene for the X-linked (X EDMD) form of EDMD, with several nuclear envelope proteins and with chromatin. Despite their widespread distribution and their role in nuclear architecture, alterations of lamin A/C are responsible for a number of very specific but quite heterogeneous disorders. The first laminopathy was the autosomal dominant form of Emery-Dreifuss muscular dystrophy (EDMD), a genetic disorder characterised by the clinical triad of early onset contractures, progressive muscular wasting and weakness with humeroperoneal distribution and cardiac conduction defects.3 The finding that emerin, an inner nuclear envelope protein, and LMNA were both involved in EDMD suggested that the lamins may represent specific and relevant factors in cardiac and skeletal muscle and that integrity of the nuclear membrane and associated structures is specifically required for muscle function. However, later on it was found that besides autosomal dominant Emery–Dreifuss muscular dystrophy (AD-EDMD), mutations in LMNA are responsible for six other disorders: limb girdle muscular dystrophy 1B, (LGMD1B),4,5 dilated cardiomyopathy with conduction system disease, (DCM-CD),6 Dunningan-type familial partial lipodystrophy,7–9 one recessive axonal form of Charcot-Marie-Tooth neuropathy,10 mandibuloacral dysplasia,11 and Hutchinson Gilford progeria.12,13 Despite the very different phenotypic consequences of mutations in LMNA , and the quite large number of mutations identified, no genotype/phenotype correlation has been demonstrated, pointing to the role of factors other than lamins A and C in determining the different tissue specific phenotypes. …