emerin and Death--Sudden--Cardiac

Emery-Dreifuss muscular dystrophy (EDMD) is an inherited muscular disorder characterized by the triad of progressive weakness in humero-peroneal muscles, early onset contractures and cardiomyopathy with conduction block that shows a high risk of sudden death. In 1994, the gene responsible for X-linked EDMD has been identified to Xq28 (designated as STA), that encodes a serine-rich protein of 254 amino acids, named emerin. In 1996, we discovered a nuclear membrane localization of emerin in the normal skeletal, cardiac and smooth muscles, but not in the tissues from patients with X-linked EDMD who had a nonsense mutation in the gene. In conclusion, molecular and genetic analyses of emerin are essential for accurate diagnosis of patients with EDMD.

Topics: Cardiomyopathies; Death, Sudden, Cardiac; Genes, Recessive; Humans; Membrane Proteins; Muscular Dystrophies; Muscular Dystrophy, Emery-Dreifuss; Mutation; Nuclear Proteins; Thymopoietins; X Chromosome

Emery Dreifuss muscular dystrophy (EDMD) is a hereditary muscular disorder, characterized by contractures, progressive muscular wasting and cardiac involvement. The majority of EDMD patients harbor mutations in the lamin A/C (LMNA) and emerin (STA) genes. Emerging data implicate mutations in FHL1 (four and a half LIM protein 1) gene, located in chromosome Xq26, in EDMD pathogenesis. FHL1 is mainly expressed in striated and cardiac muscle, and plays an important role in sarcomeric protein synthesis, maintenance of cellular integrity, intracellular signaling and genetic transcription pathways. We report the identification of a novel nonsense mutation in FHL1 gene, associated with left ventricular hypertrophy and a family history of stroke and sudden cardiac death. The management implications of this diagnosis are also discussed.

Topics: Adult; Chromosomes, Human, X; Codon, Nonsense; Death, Sudden, Cardiac; Humans; Hypertrophy, Left Ventricular; Intracellular Signaling Peptides and Proteins; Lamin Type A; LIM Domain Proteins; Male; Membrane Proteins; Muscle Proteins; Muscular Dystrophy, Emery-Dreifuss; Myocardium; Nuclear Proteins; Pedigree; Phenotype; Signal Transduction

The STA gene encodes emerin and is one of the genes that is affected in Emery-Dreifuss muscular dystrophy (EDMD). Although it has been reported that EDMD caused by the STA gene mutation is associated with X-linked recessive inheritance, the genotype-phenotype correlations, with special reference to cardiac manifestations, are not well defined.. We identified 16 carriers (7 male and 9 female) with a nonsense mutation in exon 6 of the STA gene in 2 EDMD families. Pacemakers were required for treatment of bradyarrhythmias in all 7 male carriers and in 2 of the 9 female carriers. In addition, 2 of the 9 female carriers displayed atrial fibrillation. In these 2 families, 3 males without pacemaker implantation, who were not tested genetically, had died suddenly. In these family members, the majority of carriers with the mutation had not been clinically diagnosed as having EDMD before genetic testing because of extremely mild or nonexistent skeletal myopathy.. EDMD caused by this mutation is characterized by atypical clinical features and incomplete penetrance of the clinical phenotype and may result in serious cardiac complications, including sudden death. Approaches to preventing possible sudden death in carriers with the STA gene mutation require further study.

Topics: Adolescent; Adult; Aged; Arrhythmias, Cardiac; Cardiomyopathies; Child, Preschool; Codon, Nonsense; Death, Sudden, Cardiac; Family Health; Female; Heart Atria; Heart Block; Heterozygote; Humans; Incidence; Male; Membrane Proteins; Middle Aged; Muscular Dystrophy, Emery-Dreifuss; Nuclear Proteins; Pacemaker, Artificial; Pedigree; Penetrance; Phenotype; Thymopoietins