Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy

Abstract

Emery-Dreifuss muscular dystrophy (EMD) is a condition characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block. The disease was described for the first time as an X-linked muscular dystrophy, but autosomal dominant and autosomal recessive forms were reported. The genes for X-linked EMD and autosomal dominant EMD (AD-EMD) were identified. We report here that heterozygote mutations in LMNA, the gene for AD-EMD, may cause diverse phenotypes ranging from typical EMD to no phenotypic effect. Our results show that LMNA mutations are also responsible for the recessive form of the disease. Our results give further support to the notion that different genetic forms of EMD have a common pathophysiological background. The distribution of the mutations in AD-EMD patients (in the tail and in the 2A rod domain) suggests that unique interactions between lamin A/C and other nuclear components exist that have an important role in cardiac and skeletal muscle function.

Figure 1

Chromatograms of the portions of the sequencing gels showing the presence of mutations below the pedigrees of the families of patient MG (a) and of patient PD (b). The position of the mutation is indicated (arrow). Sequences were performed and analyzed as described by Bione et al. (1995).

Figure 2

Schematic representation of the structural organization of lamin A/C and of the position of the mutations found. The four mutations described by Bonne et al. (1999) are Q6X, R453W, R527P (2X), and L530P. When mutations were found repeatedly, the number of patients is indicated in brackets. α-helical regions are shown (slash marks), as are conserved sequences in 1A and 2B (blackened squares). CBR = chromatin-binding region; NLS = nuclear localization signal.