emerin and Heart-Diseases

Mutations in the lamin A/C gene (LMNA) are known to be involved in several diseases such as Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy type 1B and dilated cardiomyopathies with conduction disease, with considerable phenotype heterogeneity. Here we report on a novel autosomal dominant mutation in LMNA in two direct relatives presenting with different clinical phenotypes, characterized by severe life-threatening limb-girdle muscle involvement and cardiac dysfunction treated with heart transplantation in the proband, and by ventricular tachyarrhythmias with preserved cardiac and skeletal muscle function in her young son. To our knowledge, this is the first report of a duplication in the LMNA gene. The two phenotypes described could reflect different clinical stages of the same disease. We hypothesize that early recognition and initiation of therapeutic manoeuvres in the younger patient may retard the rate of progression of the cardiomyopathy.

Topics: Adult; Amino Acid Sequence; Cardiomyopathy, Dilated; Electrocardiography; Female; Gene Duplication; Heart; Heart Diseases; Heart Transplantation; Humans; Immunohistochemistry; Lamin Type A; Membrane Proteins; Middle Aged; Molecular Sequence Data; Muscle Weakness; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Nuclear Proteins; Pedigree; Phenotype; Stroke Volume; Tomography, X-Ray Computed

Mutations in the EMD and LMNA genes, encoding emerin and lamins A and C, are responsible for the X-linked and autosomal dominant and recessive forms of Emery-Dreifuss muscular dystrophy (EDMD). LMNA mutations can also lead to several other disorders, collectively termed laminopathies, involving heart, fat, nerve, bone, and skin tissues, and some premature ageing syndromes.. Fourteen members of a single family underwent neurologic, electromyographic, and cardiologic assessment. Gene mutation and protein expression analyses were performed for lamins A/C and emerin.. Clinical investigations showed various phenotypes, including isolated cardiac disease (seven patients), axonal neuropathy (one patient), and a combination of EDMD with axonal neuropathy (two patients), whereas five subjects remained asymptomatic. Genetic analyses identified the coincidence of a previously described homozygous LMNA mutation (c.892C-->T, p. R298C) and a new in-frame EMD deletion (c.110-112delAGA, p. delK37), which segregate independently. Analyses of the contribution of these mutations showed 1) the EMD codon deletion acts in X-linked dominant fashion and was sufficient to induce the cardiac disease, 2) the combination of both the hemizygous EMD and the homozygous LMNA mutations was necessary to induce the EDMD phenotype, 3) emerin was present in reduced amount in EMD-mutated cells, and 4) lamin A/C and emerin expression was most dramatically affected in the doubly mutated fibroblasts.. This highlights the crucial role of lamin A/C-emerin interactions, with evidence for synergistic effects of these mutations that lead to Emery-Dreifuss muscular dystrophy as the worsened result of digenic mechanism in this family.

Topics: Adolescent; Adult; Blotting, Western; Electromyography; Female; Fibroblasts; Fluorescent Antibody Technique; Genotype; Heart Diseases; Humans; Lamin Type A; Male; Membrane Proteins; Middle Aged; Muscle, Skeletal; Muscular Dystrophy, Emery-Dreifuss; Mutation; Nuclear Proteins; Pedigree; Peripheral Nervous System Diseases; Phenotype; Polymerase Chain Reaction

Mutations in the lamin A/C gene have been reported in a variety of disorders including autosomal dominant Emery-Dreifuss muscular dystrophy and autosomal dominant limb girdle muscular dystrophy with cardiac conduction block or limb girdle muscular dystrophy type 1B (LGMD1B). However, how these mutations are involved in developing these diseases is not known. We examined morphological changes of the skeletal muscle in two cases of LGMD1B in a family, directing our attention to the nuclear envelope and its underlying structures where lamin A/C is located. Although conventional fluorescence microscope revealed no discernible abnormality in the distribution of emerin and lamin A/C, a serial multi-layer scanning with confocal laser scanning microscope showed an attenuated and uneven distribution of lamin A/C. Furthermore, under an electron microscope, the nuclear fibrous lamina and inner nuclear membrane were relatively indistinct compared to controls. These changes in the myonuclei may be related to pathomechanisms of the present cases.

Topics: Adult; Aged; Aged, 80 and over; Chi-Square Distribution; Family Health; Female; Fluorescent Antibody Technique; Heart Diseases; Humans; Male; Membrane Proteins; Microscopy, Confocal; Microscopy, Electron; Middle Aged; Muscular Dystrophies; Nuclear Envelope; Nuclear Lamina; Nuclear Proteins; Skeletal Muscle Ventricle; Thymopoietins

Topics: Adolescent; Adult; Arrhythmias, Cardiac; Cardiomyopathy, Dilated; Child; DNA Mutational Analysis; Heart Diseases; Humans; Lamin Type A; Lamins; Membrane Proteins; Middle Aged; Muscular Dystrophies; Muscular Dystrophy, Emery-Dreifuss; Mutation; Nuclear Proteins; Phenotype; Thymopoietins

The purpose of this study was to search for STA gene defects in three families with clinically typical Emery-Dreifuss muscular dystrophy. Emery-Dreifuss is an X-linked muscular dystrophy with humeroperoneal weakness and life-threatening, but treatable, cardiac abnormalities in male patients and in female carriers. The defect is in the gene coding for emerin, a 254 amino acid protein of unknown function. Complementary and genomic DNA from T lymphocytes from the reported patients and their family members were amplified, cloned, and sequenced. A novel mutation, a 26 base-pair deletion in three brothers and a carrier mother, was detected in one family. A splicing mutation with one base pair insertion and a five base-pair deletion, which have been described previously, were found in the second and third families, respectively. The additional novel mutation detected and the findings of three different mutations in these three families support the idea of genetic heterogeneity of Emery-Dreifuss muscular dystrophy with different mutations in different families.

Topics: Adolescent; Adult; Child; Consanguinity; DNA Mutational Analysis; Genetic Linkage; Heart Diseases; Humans; Male; Membrane Proteins; Muscular Dystrophies; Muscular Dystrophy, Emery-Dreifuss; Nuclear Proteins; Sequence Deletion; Thymopoietins; X Chromosome