emerin and Cardiomyopathies

The human genome is contained within the nucleus and is separated from the cytoplasm by the nuclear envelope. Mutations in the nuclear envelope proteins emerin and lamin A cause a number of diseases including premature aging syndromes, muscular dystrophy, and cardiomyopathy. Emerin and lamin A are implicated in regulating muscle- and heart-specific gene expression and nuclear architecture. For example, lamin A regulates the expression and localization of gap junction and intercalated disc components. Additionally, emerin and lamin A are also required to maintain nuclear envelope integrity. Demonstrating the importance of maintaining nuclear integrity in heart disease, atrioventricular node cells lacking lamin A exhibit increased nuclear deformation and apoptosis. This review highlights the present understanding of lamin A and emerin function in regulating nuclear architecture, gene expression, and cell signaling and discusses putative mechanisms for how specific mutations in lamin A and emerin cause cardiac- or muscle-specific disease.

Topics: Aging, Premature; Animals; Apoptosis; Atrioventricular Node; Cardiomyopathies; Gene Expression Regulation; Genome, Human; Humans; Lamin Type A; Membrane Proteins; Muscular Dystrophies; Mutation; Myocardium; Nuclear Lamina; Nuclear Proteins; Organ Specificity; Signal Transduction; Syndrome

Topics: Animals; Cardiomyopathies; Cytoskeleton; Dystrophin; Humans; Lamin Type A; Membrane Proteins; Mutation; Myocardium; Nuclear Proteins

Emery-Dreifuss muscular dystrophy (EDMD) is an inherited disorder characterized by the clinical triad of life-threatening progressive cardiomyopathy with conduction defect, early onset joint contractures and slow progressive muscle weakness in scapulo-humero-peroneal distribution. Cardiomyopathy in EDMD is usually noticed after the second to third decade of life, and becomes worse with age. Permanent auricular paralysis occurs frequently and is considered a hallmark of EDMD cardiomyopathy. Cardiac involvement may also occur in female carriers. In autopsy cases, enlargement of the atria with remarkable thinning have been observed. Identification of the gene responsible for X-linked EDMD (X-EDMD) and the protein product, emerin, provided a diagnostic clue for EDMD. Since the emerin gene is rather small, the entire sequence can easily be surveyed. Western blot and immunohistochemistry show an absence of emerin in muscle and skin tissues and oral exfoliating cells in male patients with X-EDMD, and a reduction of the protein content with a mosaic expression pattern in female carriers. Emerin anchors at the inner nuclear membrane of cardiac, skeletal and smooth muscles, and interacts with lamins and nucleoplasm, thereby possibly maintaining the mechanical stability of the nuclear membrane of muscle cells that shows rigorous contraction/relaxation. More recently, positive emerin staining at the cardiac demosomes and fasciae adherentes was noticed in addition to the specific localization at the inner nuclear membrane. This localization implies a physiological role for the protein in cardiac conduction.

Topics: Cardiomyopathies; Genetic Linkage; Humans; Membrane Proteins; Muscular Dystrophies; Muscular Dystrophy, Emery-Dreifuss; Nuclear Proteins; Thymopoietins; X Chromosome

Emery-Dreifuss muscular dystrophy (EDMD) is the third most common X-linked muscular dystrophy. This disorder is characterized by childhood onset of early contractures, humeroperoneal muscle atrophy, and cardiac conduction abnormalities. Weakness is slowly progressive, but there is a broad spectrum of clinical severity. Patients and carriers are at risk of sudden death. Regular cardiac evaluation is mandatory to assess the risk of cardiac arrhythmias. Unique atrial pathology is seen at autopsy. The mutated gene in EDMD is localized to the long arm of the X chromosome. Mutations in the gene lead to abolished synthesis of the gene product, emerin. Emerin is localized to the nuclear membrane of skeletal, cardiac, and smooth muscle. The term Emery-Dreifuss syndrome describes patients who have the EDMD phenotype without X-linked inheritance. There is no treatment for the underlying disease, but early placement of pacemakers may be lifesaving.

Topics: Atrophy; Cardiomyopathies; Creatine Kinase; Genetic Linkage; Humans; Membrane Proteins; Muscle, Skeletal; Muscular Dystrophy, Emery-Dreifuss; Mutation; Nuclear Proteins; Phenotype; Polymerase Chain Reaction; Thymopoietins; X Chromosome

Emery-Dreifuss syndrome is a heterogeneous entity characterized by the following clinical triad: early contracture of the elbows. Achilles tendons and postcervical muscles; slowly progressive muscle wasting and weakness with a humeroperoneal distribution early in the course of disease; and a cardiomyopathy usually presenting as an atrioventricular block ranging from sinus bradycardia to complete heart block. As the heart block is the major problem, insertion of a cardiac pacemaker can be life saving. Recent advances through genetic and immunochemical studies have provided valuable clues to the understanding and the early diagnosis of this disease.

Topics: Cardiomyopathies; Contracture; Diagnosis, Differential; Genes, Recessive; Heart Block; Humans; Membrane Proteins; Muscular Dystrophies; Nuclear Proteins; Sex Chromosome Aberrations; Thymopoietins; X Chromosome

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

Two brothers are reported suffering from X-linked Emery-Dreifuss muscular dystrophy caused by a 59bp deletion eliminating nucleotides 329-388 of the STA gene. Besides the typical findings for Emery-Dreifuss muscular dystrophy, both patients showed an unusual early onset of cardiac symptoms at age 6 and 9 years, respectively, coinciding with unusual high creatine kinase. A cardiological follow up showed worsening of the cardiac condition in the beginning of the second decade. The two boys described here belong to the very few Emery-Dreifuss muscular dystrophy patients with early onset of cardiac involvement and contribute to the variability of cardiac symptoms in Emery-Dreifuss muscular dystrophy.

Topics: Achilles Tendon; Adolescent; Cardiomyopathies; Child; Chromosomes, Human, X; DNA Mutational Analysis; Elbow; Electroencephalography; Follow-Up Studies; Humans; Male; Membrane Proteins; Muscular Dystrophy, Emery-Dreifuss; Nuclear Proteins; Pedigree; Sequence Deletion; Thymopoietins

Mutations in the nuclear envelope genes encoding. Targeted exon sequencing was performed in 87 probands with familial sick sinus syndrome (n=36) and a progressive cardiac conduction defect (n=51).. We identified 3 X-linked recessive. Cardiac emerinopathy is a novel nonsyndromic X-linked progressive atrial standstill associated with LVNC and increased risk of thromboembolism.

Topics: Adolescent; Adult; Aged; Cardiac Conduction System Disease; Cardiomyopathies; Child; Female; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Heart Atria; Heart Block; Humans; Isolated Noncompaction of the Ventricular Myocardium; Male; Membrane Proteins; Middle Aged; Mutation; Nuclear Proteins; Phenotype; Sick Sinus Syndrome; Stroke; Thromboembolism; X-Linked Emery-Dreifuss Muscular Dystrophy; Young Adult

Emery-Dreifuss muscular dystrophy (EDMD) is a hereditary myopathy characterized as triad of muscular dystrophy, joint contractures, and conduction cardiomyopathy. In this study, we diagnosed a X-linked recessive EDMD patient with severe conduction cardiomyopathy while noteless muscular and joint disorders.. A Chinese cardiomyopathy family spanning four generations was enrolled in the study. Targeted next-generation sequencing (NGS) was performed to identify the underlying mutation in the proband and validated by Sanger sequencing. Segregation analysis was applied to all 13 participants.. A novel frameshift mutation (c.253_254insT, p.Y85Lfs*8) of emerin gene (EMD) was found and co-segregated with family members. Other than the typical manifestations of X-linked EDMD, this patient presented inconspicuous muscular disorders which were later diagnosed after the mutation been identified.. This study enriches the EMD gene mutation database and reminds us of the possibility of EDMD while encountering patients with severe heart rhythm defects or dilated cardiomyopathy of unknown etiology, even if they have neither obvious skeletal muscle disorder nor joint involvement.

Topics: Asian People; Cardiac Conduction System Disease; Cardiomyopathies; Echocardiography; Family; Female; Humans; Male; Membrane Proteins; Middle Aged; Muscle, Skeletal; Muscular Dystrophy, Emery-Dreifuss; Mutation; Nuclear Proteins

Emery-Dreifuss muscular dystrophy (EDMD) is a neuromuscular disease characterized by early contractures, slowly progressive muscular weakness and life-threatening cardiac arrhythmia that can develop into cardiomyopathy. In X-linked EDMD (EDMD1), female carriers are usually unaffected. Here we present a clinical description and in vitro characterization of a mildly affected EDMD1 female carrying the heterozygous EMD mutation c.174_175delTT; p.Y59* that yields loss of protein. Muscle tissue sections and cultured patient myoblasts exhibited a mixed population of emerin-positive and -negative cells; thus uneven X-inactivation was excluded as causative. Patient blood cells were predominantly emerin-positive, but considerable nuclear lobulation was observed in non-granulocyte cells - a novel phenotype in EDMD. Both emerin-positive and emerin-negative myoblasts exhibited spontaneous differentiation in tissue culture, though emerin-negative myoblasts were more proliferative than emerin-positive cells. The preferential proliferation of emerin-negative myoblasts together with the high rate of spontaneous differentiation in both populations suggests that loss of functional satellite cells might be one underlying mechanism for disease pathology. This could also account for the slowly developing muscle phenotype.

Topics: Adolescent; Adult; Age of Onset; Antigens, CD; Autoantigens; Cardiomyopathies; Cell Cycle Proteins; Cell Differentiation; Cell Proliferation; Cells, Cultured; Child; Family Health; Female; Flow Cytometry; Humans; Ki-67 Antigen; Lamin Type A; Magnetic Resonance Imaging; Male; Membrane Proteins; Muscular Dystrophy, Emery-Dreifuss; Myoblasts; Nuclear Proteins; RNA, Small Interfering; Transfection; Young Adult

Cardiac involvement in X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) usually includes arrhythmias but not dilative cardiomyopathy (dCMP). Here, we report an X-EDMD patient with severe dCMP and life-threatening ventricular arrhythmias associated with other phenotypic features unusual for X-EDMD.. A 46-year-old patient with X-EDMD due to the known splice-site mutation c.449 + 1G>A in the emerin gene experienced palpitations for the first time at the age of 21 years, and a first syncope at the age of 23 years. He was started on phenprocoumon due to atrial fibrillation and systolic dysfunction. At the age of 28 years he received his first pacemaker. Echocardiography at the age of 36 years showed left ventricular dilatation, enlarged atria, myocardial thickening, 28% ejection fraction and diastolic dysfunction. dCMP was suspected. At the age of 38 years, a cardiac resynchronization therapy system was implanted, which was upgraded to an implantable cardioverter defibrillator (ICD) because of ventricular tachycardias (at the age of 42 years). During the following months, the ICD discharged 30 times due to ventricular tachycardias. In May 2013, he required recurrent cardio-pulmonary resuscitation because ventricular fibrillation occurred with no discharge of the ICD. He was listed for heart transplantation. He also had hypothyroidism, liver hemangiomas, thrombopenia, anemia and diverticulosis.. X-EDMD may occur along with dCMP. An ICD may be ineffective for ventricular fibrillation in X-EDMD. X-EDMD may be associated with unusual, atypical phenotypic features.

Topics: Arrhythmias, Cardiac; Cardiomyopathies; Humans; Male; Membrane Proteins; Middle Aged; Muscular Dystrophy, Emery-Dreifuss; Mutation; Nuclear Proteins; RNA Splice Sites

Mutations in genes encoding A-type lamins and emerin cause cardiomyopathy and muscular dystrophy. We previously showed activation of the extracellular signal-regulated kinase (ERK) branch of the mitogen-activated protein kinase (MAPK) cascade in hearts of mice with mutations in these genes. Here, we tested the hypothesis that reducing A-type lamins and emerin in cultured cells activate ERK signaling.. We used siRNA to knockdown A-type lamins and emerin in HeLa and C2C12 cells. Activation of ERK was assessed by immunoblotting and immunofluorescence microscopy with antibodies against phosphorylated protein and by using real-time RT-PCR to measure RNAs encoded by genes for transcription factors stimulated by ERK.. Knockdown of A-type lamins and emerin in HeLa and C2C12 stimulated phosphorylation and nuclear translocation of ERK as well as activation of genes encoding downstream transcription factors. A MAPK/ERK kinase (MEK) inhibitor reduced ERK phosphorylation in cells with reduced expression of A-type lamins and emerin.. These results provide proof for the hypothesis that altered expression of emerin and A-type lamins activates ERK signaling, which in turn can cause cardiomyopathy.. ERK is a potential target for the pharmacological treatment of cardiomyopathy caused by mutations in the genes encoding emerin and A-type lamins.

Topics: Animals; Cardiomyopathies; Cell Line; Gene Expression; HeLa Cells; Humans; Lamin Type A; MAP Kinase Signaling System; Membrane Proteins; Mice; Mitogen-Activated Protein Kinases; Mutation; Nuclear Proteins; RNA, Small Interfering

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

Mutations in LMNA, the gene that encodes nuclear lamins A and C, cause up to eight different diseases collectively referred to as "laminopathies." These diseases affect striated muscle, adipose tissue, peripheral nerve, and bone, or cause features of premature aging. We investigated the consequences of LMNA mutations on nuclear architecture in skin fibroblasts from 13 patients with different laminopathies. Western-blotting showed that none of the mutations examined led to a decrease in cellular levels of lamin A or C. Regardless of the disease, we observed honeycomb nuclear structures and nuclear envelope blebs in cells examined by immunofluorescence microscopy. Concentrated foci of lamin A/C in the nucleoplasm were also observed. Only mutations in the head and tail domains of lamins A and C significantly altered the nuclear architecture of patient fibroblasts. These results confirm that mutations in lamins A and C may lead to a weakening of a structural support network in the nuclear envelope in fibroblasts and that nuclear architecture changes depend upon the location of the mutation in different domains of lamin A/C.

Topics: Adolescent; Adult; Blotting, Western; Cardiomyopathies; Cell Count; Cell Nucleus; Child; Female; Fibroblasts; Humans; Lamin Type A; Lipodystrophy; Male; Membrane Proteins; Microscopy, Fluorescence; Middle Aged; Muscular Dystrophies; Mutation; Nuclear Envelope; Nuclear Proteins; Phenotype; Thymopoietins

Hauptmann-Thannhauser muscular dystrophy is characterized by the clinical triad of early-onset contractures of elbow, Achilles tendons, and cervical spine, slowly progressive humeroperoneal muscle wasting and weakness, and life-threatening cardiac involvement with conduction blocks manifesting in the third decade. Hauptmann-Thannhauser muscular dystrophy is due to mutations in the LMNA gene affecting the nuclear envelope proteins lamin A and C. We present a 16-year-old German boy with typical muscular involvement and contractures and typical course of Hauptmann-Thannhauser muscular dystrophy due to the novel missense mutation R401C. The data of this family suggest a lower penetrance of muscular and especially cardiac symptoms than expected. Autosomal-dominant Hauptmann-Thannhauser muscular dystrophy and X-chromosomal Emery-Dreifuss muscular dystrophy are not clearly distinguishable by phenotypic criteria. Other muscular diseases associated with contractures and congenital or childhood onset are reviewed.

Topics: Adolescent; Biopsy; Cardiomyopathies; Cell Nucleus; Contracture; Humans; Lamin Type A; Male; Membrane Proteins; Muscle Weakness; Muscle, Skeletal; Muscular Atrophy; Muscular Dystrophy, Emery-Dreifuss; Mutation, Missense; Neurologic Examination; Nuclear Proteins; Pedigree; Phenotype; Syndrome; Thymopoietins

A screening for mutation in the X-linked Emery-Dreifuss muscular dystrophy (X-EMD) gene was performed among patients affected with severe heart rhythm defects and/or dilated cardiomyopathy. Patients were selected from the database of the Department of Cardiology of the University Hospital Brno. One patient presented a mutation in the X-EMD gene and no emerin in his skeletal muscle. The patient had a severe cardiac disease but a very mild muscle disorder that had not been diagnosed until the mutations was found. This case shows that mutations in X-EMD gene, as it was shown for autosomal-dominant EMD, can cause a predominant cardiac phenotype.

Topics: Adult; Cardiomyopathies; Genetic Linkage; Heart Conduction System; Humans; Male; Membrane Proteins; Muscle, Skeletal; Muscular Dystrophy, Emery-Dreifuss; Mutation; Nuclear Proteins; Thymopoietins; X Chromosome