Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
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The Emery-Dreifuss Muscular Dystrophy (EDMD) is an X-linked recessive muscular disorder characterized by early contractures of the elbows, Achilles tendons and postcervical muscles, slowly progressing muscle wasting and weakness and a cardiomyopathy characterized by conduction defects. Heart block is a frequent cause of death. Finding of mutations in one of the transcripts in the critical region in distal Xq28 led to the identification of the gene responsible for the disease. We now report the sequence of the gene which is 2100 bp long and the development of a set of primers to amplify and sequence the gene from patients' DNA. Eight unrelated X-linked familial cases were studied and they all carried different mutations, showing that lack of emerin in cardiac and skeletal muscle is the cause of the X-linked disease. No mutations were found in a family where the female carrier was affected nor in a sporadic case with a well established diagnosis of EDMD. Our findings suggest genetic heterogeneity of EDMD, and that at least two genes, the X-linked STA gene and one unidentified autosomal gene, are responsible for the disease.
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PMID:Identification of new mutations in the Emery-Dreifuss muscular dystrophy gene and evidence for genetic heterogeneity of the disease. 859 7

Emery-Dreifuss muscular dystrophy (EMD) is an X-linked disorder characterized by contractures, progressive muscle weakness and cardiomyopathy. The emerin gene, located in human Xq28, is approximately 2 kb in length, is composed of 6 exons and falls within a 219-kb region that has been completely sequenced. Immediately centromeric to emerin is the 26-kb filamin gene (FLN1), composed of 48 exons and encoding the actin-binding protein 280 (refs 7,8). Flanking this 48-kb FLN1/emerin region are two large inverted repeats, each 11.3 kb, that exhibit > 99% sequence identity. The high level of genomic detail in this region allowed us to characterize the first complete emerin gene deletion mutation that also involved a partial duplication of the nearby FLN1 gene. This rearrangement could be explained by mispairing of the large inverted repeats, followed by double recombination among one set of mispaired repeats and internal sequences. Furthermore, our characterization of this rare DNA rearrangement revealed a more common result of the mispairing of these large inverted repeats--recombination contained within the inverted repeats leading to the maintenance of repeat sequence homogeneity and inversion of the 48-kb FLN1/emerin region. The presence of this frequent inversion, found in the heterozygous state in 33% of females, helps to explain the discrepancies observed between the genetic and physical map distances in this region of the X chromosome. It also illustrates the biological insights which can be gleaned by sequencing the human genome.
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PMID:Emerin deletion reveals a common X-chromosome inversion mediated by inverted repeats. 914 Mar 86

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked inherited disease characterized by early contracture of the elbows, Achilles tendons and post-cervical muscles, slow progressive muscle wasting and weakness and cardiomyopathy presenting with arrhythmia and atrial paralysis: heart block can eventually lead to sudden death. The EDMD geneencodes a novel ubiquitous protein, emerin, which decorates the nuclear rim of many cell types. Amino acid sequence homology and cellular localization suggested that emerin is a member of the nuclear lamina-associated protein family. These findings did not explain the role of emerin nor account for the skeletal muscle- and heart-specific clinical manifestations associated with the disorder. Now we report that emerin localizes to the inner nuclear membrane, via its hydrophobic C-terminal domain, but that in heart and cultured cardiomyocytes it is also associated with the intercalated discs. We propose a general role for emerin in membrane anchorage to the cytoskeleton. In the nuclear envelope emerin plays a ubiquitous and dispensable role in association of the nuclear membrane with the lamina. In heart its specific localization to desmosomes and fasciae adherentes could account for the characteristic conduction defects described in patients.
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PMID:Heart-specific localization of emerin: new insights into Emery-Dreifuss muscular dystrophy. 936 Oct 31

Emery-Dreifuss muscular dystrophy (EMD) is an X-linked disorder characterized by contractures, progressive weakness and cardiomyopathy. EMD is caused by mutations in the 2 kb emerin gene that is located within human Xq28. Emerin is immediately distal to the 26 kb filamin gene, and flanking the filamin-emerin region are two large inverted repeats. This entire region previously has been found to be inverted in approximately 20% of X chromosomes, presumably mediated by the inverted repeats. Only one complete emerin deletion has been reported previously. It was found to be due to a complex rearrangement involving the inverted repeats which partially duplicated filamin. We report here two additional EMD patients who have large deletions of 20 and 34 kb, respectively. Unlike the previously reported deletion, these deletions appear to be simple deletions, with each breakpoint junction showing only 2 bp of overlap, suggesting an end-joining mechanism. However, the two deletions were found on each of the two inverted backgrounds. The 20 kb deletion includes the entire emerin gene and extends well into most of the distal inverted repeat. In contrast, the 34 kb deletion occurs on the inverted X chromosome and extends centromeric, well beyond the proximal inverted repeat. In addition, at least three nearby putative genes detected by previous sequence analysis are deleted among these patients but without obvious deviation from a typical EMD phenotype. Similarly to the previously reported deletion, filamin remains intact in these two deletions. All three deletions involve distinct breakpoints within the 4.7 kb filamin-emerin intergenic region, suggesting that loss of filamin is a lethal event. Thus, the close proximity of filamin to emerin may place constraints upon potential emerin deletions and probably accounts for the rarity of complete emerin deletions in EMD patients.
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PMID:Emerin deletions occurring on both Xq28 inversion backgrounds. 938 14

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.
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PMID:[Emery-Dreifuss muscular dystrophy]. 943 33

Emery-Dreifuss muscular dystrophy (EMD) is an inherited myopathy characterised by muscle contractures, progressive muscle wasting and weakness, with humeroperoneal distribution. Cardiac arrhythmia and heart conduction block are also important characteristics of this disease. The X-linked form of EMD is caused by the absence of emerin, encoded by the STA gene (Xq28). Emerin is normally localized in muscle and other tissues at the nuclear rim. Currently, muscle and skin biopsies are used for the immunohistochemical diagnosis. We demonstrate that emerin is present in the cheek oral mucosa, in the exfoliating epithelial cells, and we propose the collection of these cells as a new method for the diagnosis of X-linked EMD patients and the detection of carriers by immunofluorescence techniques: smears from healthy subjects contained about 98% emerin-positive cells, those from X-linked EMD patients contained none and those from carriers contained about 45%. The technique is completely non-invasive, simple, repeatable and inexpensive.
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PMID:Oral exfoliative cytology for the non-invasive diagnosis in X-linked Emery-Dreifuss muscular dystrophy patients and carriers. 960 58

Emery-Dreifuss muscular dystrophy is an X-linked neuromuscular disorder caused by defects in the STA gene on Xq28, which codes for a nuclear protein named emerin. Affected patients usually present in early adolescence with scapulo-peroneal muscle weakness and wasting, and contractures of the tendo Achilles, elbows and paraspinal muscles, resulting in spine rigidity. We present here a case of Emery-Dreifuss muscular dystrophy with an unusually severe, early presentation. He presented at 2.5 years with predominantly proximal weakness and mild equinovarus deformity of the right foot. Serum creatine kinase activity was elevated (1994 IU/I) and a muscle biopsy at the age of 4 years showed marked dystrophic abnormalities. Normal expression of dystrophin, and no detectable deletion in the corresponding gene, excluded a diagnosis of Duchenne muscular dystrophy. Similarly, normal expression of alpha-sarcoglycan made a limb-girdle muscular dystrophy caused by a defect in a sarcoglycan unlikely. Several years later, examination of the proband's maternal cousin, aged 14 years, suggested Emery-Dreifuss muscular dystrophy. This was confirmed in both affected boys by the absence of emerin in muscle and leucocytes, and identification of a mutation in exon 4 of the STA gene. Carrier status in both mothers was also confirmed by mutational and protein analysis. Emery-Dreifuss muscular dystrophy should therefore be considered in the differential diagnosis of cases of early onset muscular dystrophy, even in the absence of the typical clinical features.
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PMID:Early presentation of X-linked Emery-Dreifuss muscular dystrophy resembling limb-girdle muscular dystrophy. 960 59

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and a cardiomyopathy with conduction blocks which is life-threatening. Two modes of inheritance exist, X-linked (OMIM 310300) and autosomal dominant (EDMD-AD; OMIM 181350). EDMD-AD is clinically identical to the X-linked forms of the disease. Mutations in EMD, the gene encoding emerin, are responsible for the X-linked form. We have mapped the locus for EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype in four other small families was potentially linked to this locus. This region contains the lamin A/C gene (LMNA), a candidate gene encoding two proteins of the nuclear lamina, lamins A and C, produced by alternative splicing. We identified four mutations in LMNA that co-segregate with the disease phenotype in the five families: one nonsense mutation and three missense mutations. These results are the first identification of mutations in a component of the nuclear lamina as a cause of inherited muscle disorder. Together with mutations in EMD (refs 5,6), they underscore the potential importance of the nuclear envelope components in the pathogenesis of neuromuscular disorders.
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PMID:Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. 1008 Jan 80

Emery-Dreifuss muscular dystrophy is a neuromuscular disorder that has three characteristics: (a) early contracture of the elbows, Achilles tendons and postcervical muscles; (b) slowly progressive wasting and weakness of skeletal muscle; and (c) cardiomyopathy with severe conduction block. The responsible gene for the X-linked recessive form of this disease encodes an inner nuclear membrane protein named emerin. Although emerin is absent in tissues from patients with this disorder, it remains obscure why the loss of this widely expressed protein affects selectively skeletal muscle, heart and joints. As the first step to address this question, we examined the molecular regions of emerin that are essential for nuclear membrane targeting and stability of the protein. We found that the C-terminal hydrophobic region was necessary, but not sufficient, for nuclear membrane anchoring and stability of the protein. In the absence of this transmembrane domain, the upstream nucleoplasmic domain showed no firm association with the nuclear rim, but showed the tendency to accumulate at the nucleolus-like structures. Furthermore, proper targeting of emerin to the nuclear membrane required the latter half of the nucleoplasmic domain. These characteristics are distinct from those of lamina-associated polypeptide 2. Our findings indicate that emerin has distinct interactions with the inner nuclear membrane components that may be required for the stability and function of rigorously moving nuclei in tissues such as skeletal muscle, heart and joints.
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PMID:Distinct regions specify the nuclear membrane targeting of emerin, the responsible protein for Emery-Dreifuss muscular dystrophy. 1009 74

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.
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PMID:Emerin and cardiomyopathy in Emery-Dreifuss muscular dystrophy. 1022 Aug 66


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