1/47. Changes at P183 of emerin weaken its protein-protein interactions resulting in X-linked Emery-Dreifuss muscular dystrophy. Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive muscular dystrophy characterized by early contractures of the elbows, Achilles tendons and spine, slowly progressive muscle wasting and weakness, and cardiomyopathy associated with cardiac conduction defects. The emerin gene has been mapped to Xq28 and encodes a 34-kDa serine-rich protein, emerin, which has been localized to the nuclear envelope in a wide variety of tissues, including skeletal and cardiac muscle. Mutations spanning the emerin gene have been identified in patients with EDMD. We present here the effect, on emerin protein expression, of two missense mutations identified in unrelated EDMD patients. These alterations predict the replacement of a proline residue at position 183 with either a histidine or a threonine. Biochemical analysis has demonstrated that the mobility and expression levels of the mutant forms of emerin are indistinguishable from that of wild-type emerin, but that they have weakened interactions with nuclear lamina components. In comparison with the usual EDMD phenotype, patients with P183 missense mutations have a later age at onset of first symptoms, elbow contractures, ankle contractures, upper limb weakness and lower limb weakness, but there is no difference for the age at onset of cardiac involvement. This is the first report of protein studies on patients with missense mutations resulting in the clinical features of EDMD. These studies demonstrate the importance of proline 183 for the proper structure/function of emerin. ( info) |
2/47. Cardiac involvement in Emery Dreifuss muscular dystrophy: a case series. Three patients with Emery Dreifuss muscular dystrophy are reported. Emery Dreifuss muscular dystrophy is an X linked muscular dystrophy, in which locomotor involvement is characteristically mild and slowly progressive. The effect on the heart becomes apparent in the teenage years and is characterised by cardiac conduction defects and infiltration of the myocardium by fibrous and adipose tissue. It first affects the atria, which results in atrial paralysis; treatment with ventricular pacing is usually needed. female carriers can develop heart problems and are at risk of sudden death. Relatives of affected patients should be offered screening with electrocardiography and echocardiography. ( info) |
3/47. Severe clinical expression in X-linked Emery-Dreifuss muscular dystrophy. X-linked Emery-Dreifuss muscular dystrophy (EDMD) is a relatively rare benign neuromuscular disorder which can vary remarkably in onset, course and severity. In the present study, a TCTAC deletion spanning the nucleotides 631-635 of the emerin gene caused an unusually severe disease phenotype including loss of ambulation and severe muscle wasting in two affected brothers. The same mutation has been reported previously in an unrelated family showing a significantly milder phenotype. The interfamilial heterogeneity in distribution and in severity of the features in the two families point to environmental or genetic modification as the cause of clinical variability in Emery-Dreifuss muscular dystrophy. ( info) |
4/47. mutation analysis in Emery-Dreifuss muscular dystrophy. 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. ( info) |
5/47. Early onset of X-linked Emery-Dreifuss muscular dystrophy in a boy with emerin gene deletion. A boy developed contractures of the Achilles tendons at 3 years and of the postcervical muscles at 7 years, although neither contractures of the elbows nor cardiac abnormality were recognized by the age of 9 years. Muscle computed tomography scanning revealed changes characteristic of muscle involvement. Emerin was not detected in the biopsied muscle, and RT-PCR and PCR-based genomic dna analyses of the emerin gene demonstrated no amplification product in the patient. These results confirmed the diagnosis of X-linked Emery-Dreifuss muscular dystrophy (EDMD), and reinforce the necessity of molecular genetic diagnosis of the membrane protein emerin in younger patients with possible EDMD before appearance of the typical symptoms, to avoid sudden cardiac death. ( info) |
6/47. Familial scapuloperoneal myopathy and mitochondrial dna defect. The authors present 13 members of 4 generations in a family with scapuloperoneal myopathy. The disease showed autosomal dominant inheritance. In all 6 patients examined, the disease began in the third decade (18-31 years). Initially the shoulder girdle was involved, and the process slowly spread to the distal part of the lower extremities in several years or decades. The facial and pelvic muscles were only moderately involved; ocular muscle involvement was absent. Myopathy was proved by electromyography and muscle biopsy. In 1 case, electrophysiological evidence of peripheral neuropathy was found, and in 3 other patients central nervous system involvement (dementia, epilepsy) and optic atrophy complicated the syndrome. In the youngest patient, a mutation could be found in the 'hot-spot region' of the muscle mitochondrial dna by polymerase chain reaction. ( info) |
7/47. Two distal mutations in the gene encoding emerin have profoundly different effects on emerin protein expression. Emerin, the product of the gene responsible for X-linked Emery-Dreifuss muscular dystrophy (EDMD), has a ubiquitous tissue distribution and is localised to the nuclear envelope. We present here the relationship between emerin protein expression, nuclear localization and clinical phenotype for two distal mutations identified in unrelated EDMD patients. The first mutation predicts the replacement of the last eight amino acids of emerin with the addition of 101 amino acids, but no emerin expression is detected. The second mutation, 35 bp upstream from the first mutation, deletes six amino acids from the transmembrane region, but in this case emerin expression is seen. Emerin from this second patient is expressed at reduced levels, mistargeted and has altered biochemical properties compared to wild type emerin. In both cases the clinical phenotype was similar to patients with typical null mutations. We discuss these data in comparison with previous reports of other C-terminal mutations in the emerin gene and suggest that the efficiency of emerin's nuclear membrane localization is affected by the hydrophobicity (and possibly length) of its transmembrane region, and a longer C-terminal tail prevents nuclear localization. ( info) |
8/47. Autosomal dominant Emery-Dreifuss dystrophy due to mutations in rod domain of the lamin A/C gene. BACKGROUND: Autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD) is a disorder characterized clinically by humeropelvic weakness, contractures, and cardiomyopathy, and genetically by mutations in the lamin A/C gene on 1q21.2-q21.3. Of the 14 lamin A/C gene mutations reported thus far, the four involving the rod domain have been associated with isolated cardiomyopathy and conduction-system disease. This is the first report of rod domain mutations in patients with the full EDMD-AD phenotype. methods: Clinical, pathologic, and genetic data are provided on two families with EDMD-AD. RESULTS: In both families, the full clinical spectrum of EDMD-AD was demonstrated. For the proband in family 1, sequence analysis detected a mutation within exon 2 of the lamin A/C gene. The missense mutation was due to a A448C base substitution causing a Thr150Pro amino acid change. For the proband of family 2, sequence analysis detected an in-frame 3-bp deletion (AAG 778-780 or 781-783) removing one of two adjacent lysine residues (K 260 or 261) of exon 4. Both mutations were in the central rod domain of the lamin A/C gene. CONCLUSIONS: Mutations in the rod domain of the lamin A/C gene may cause the full clinical spectrum of EDMD-AD. ( info) |
9/47. Unusual expression of emerin in a patient with X-linked Emery-Dreifuss muscular dystrophy. We report on a patient with the typical clinical findings of Emery-Dreifuss muscular dystrophy due to a mutation in the emerin gene that should have produced a higher molecular weight protein. Immunohistochemical analysis showed emerin localized only in the cytoplasm of muscle fibres and lymphoblastoid cells. The emerin molecule contained the nucleoplasmic domain and the transmembrane domain responsible for nuclear membrane targeting, so its incorrect localization and lack of function could be due to abnormal folding resulting in rapid degradation or inability to bind other nuclear proteins. ( info) |
10/47. Emery-Dreifuss muscular dystrophy: anatomical-clinical correlation (case report). We report on a man that had weakness of humeroperoneal distribution associated with limited range of motion of the cervical spine and elbows since he was 5 years old. At age 26 he developed tachycardia episodes. A complex arrhythmia was discovered, and a nodal ablation was done with a cardiac pacemaker implanted. The patient had an arrhythmia and sudden death followed this. Emery-Dreifuss muscular dystrophy is a rare recessive X-linked muscular disorder where mixed patterns in electromyography and muscle histology (neurogenic and/or myopathic) have caused nosological confusion. The autopsy findings are here described and correlated to the clinical features in an attempt to better understand the ambiguous findings concerning the process etiology. ( info) |