Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Observations are presented on a family with muscular weakness and wasting with an onset in childhood, predominantly affecting the proximal muscles in the upper limbs and the distal muscles in the lower. This was accompanied by contractures of the elbows and by pes cavus. Pseudohypertrophy was absent. Progression was slow, but an associated cardiomyopathy developed in adult life. Investigations favoured a myopathic basis. The inheritance was of X-linked recessive pattern and the disorder was linked with deutan colour blindness. The clinical features in this family appear to be distinctive and it is likely that the disorder represents a separate clinical entity.
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PMID:X-linked scapuloperoneal syndrome. 411 56

Muscular dystrophy is a disease characterized by wasting of muscle tissue in vivo and net loss of muscle cell protein in vitro. No comparable changes have been reported in other tissues, although all cells of affected individuals must carry the X-linked recessive mutation. On the hypothesis that predisposition to accelerated protein degradation might be latent in nonmuscle cells I investigated protein metabolism in skin fibroblasts from normal individuals and patients with Duchenne and Becker dystrophy. Under normal culture conditions rates of protein synthesis and protein degradation in the two groups of cultures were indistinguishable. Both types of cells responded to treatments that stimulate protein degradation and the extent of response was similar. Treatment with ouabain to reduce cell K+ content, and hence protein synthesis, had no effect on protein degradation in either group. Synthesis of protein was reproducibly more sensitive to ouabain in dystrophic than in normal strains, however, and the rate of protein synthesis was correlated with the steady-state K+ content. Eight out of nine dystrophic strains showed a greater sensitivity of K+ content to ouabain inhibition of the membrane Na+-K+ pump than four normal strains. This increased sensitivity could be conclusively attributed to increased efflux or decreased influx of K+, or to alterations in ouabain binding to intact cells. Others have observed membrane abnormalities in dystrophic muscle as well as in other cell types. Our findings may represent a physiological consequence of that abnormality.
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PMID:Increased ouabain sensitivity of cultured human fibroblasts from muscular dystrophy. 609 71

X-linked recessive nephrolithiasis (XRN) was described in a large kindred in which nephrolithiasis; proximal tubular dysfunction, proteinuria, nephrocalcinosis, and renal failure occur only in males. Carrier females are asymptomatic, but formal studies of them have not been done. The gene for XRN has been mapped to the pericentromeric region of the X chromosome, close to the loci for several eye disease genes. We studied six affected males, 13 carrier females, and 25 normal members of this family including 7 females whose genetic haplotype predicted them to be carriers. Studies were done in the Clinical Research Unit on a diet containing 400 mg of calcium and 2 g of sodium, and by an additional outpatient urine collection was obtained on a 1-g calcium intake. Hypercalciuria occurred in five of six affected males, 4 of 12 carrier females, and three of seven predicted carriers. Significant proteinuria was present in all affected males and in no other subjects. Low-molecular-weight proteinuria was present in all affected males: the excretion of alpha 1-microglobulin exceeded normal by 3- to 14-fold, of beta 2-microglobulin exceeded normal by 100- to 400-fold, and of retinol-binding protein exceeded normal by 1,000- to 3,000-fold. The excretion of these proteins was less strikingly elevated in carrier females, but the excretion of alpha 1-microglobulin was abnormal in 9 of 15 carriers, beta 2-microglobulin was abnormal in 12 of 15, and retinolbinding protein in was abnormal 12 of 13, and this pattern was similar in predicted carriers. The urinary concentrating ability was abnormal in four affected males with renal insufficiency but normal in all other subjects. Urinary wasting of potassium, phosphorous, and glucose occurred infrequently, and no subject was hypouricemic. Formal ophthalmologic studies were normal in five affected males. Thus, the most consistent urinary abnormalities in XRN are hypercalciuria and low-molecular-weight proteinuria, the latter of which appears to be a marker for the carrier state.
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PMID:Characterization of carrier females and affected males with X-linked recessive nephrolithiasis. 770 83

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive disorder characterized by slowly progressing contractures, wasting of skeletal muscle and cardiomyopathy. Heart block is a frequent cause of death. The disease gene has been mapped to distal Xq28. Among many genes in this region, we selected eight transcripts expressed at high levels in skeletal muscle, heart and/or brain as the best candidates for the disease. We now report, in all five patients studied, unique mutations in one of the genes, STA: these mutations result in the loss of all or part of the protein. The EDMD gene encodes a novel serine-rich protein termed emerin, which contains a 20 amino acid hydrophobic domain at the C terminus, similar to that described for many membrane proteins of the secretory pathway involved in vesicular transport.
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PMID:Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. 789 80

Duchenne muscular dystrophy (DMD) is a severe, progressive, X-linked muscle-wasting disorder with an incidence of approximately 1/3,500 male births. Females are also affected, in rare instances. The manifestation of mild to severe symptoms in female carriers of dystrophin mutations is often the result of the preferential inactivation of the X chromosome carrying the normal dystrophin gene. The severity of the symptoms is dependent on the proportion of cells that have inactivated the normal X chromosome. A skewed pattern of X inactivation is also responsible for the clinical manifestation of DMD in females carrying X;autosome translocations, which disrupt the dystrophin gene. DMD may also be observed in females with Turner syndrome (45,X), if the remaining X chromosome carries a DMD mutation. We report here the case of a karyotypically normal female affected with DMD as a result of homozygosity for a deletion of exon 50 of the dystrophin gene. PCR analysis of microsatellite markers spanning the length of the X chromosome demonstrated that homozygosity for the dystrophin gene mutation was caused by maternal isodisomy for the entire X chromosome. This finding demonstrates that uniparental isodisomy of the X chromosome is an additional mechanism for the expression of X-linked recessive disorders. The proband's clinical presentation is consistent with the absence of imprinted genes (i.e., genes that are selectively expressed based on the parent of origin) on the X chromosome.
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PMID:Uniparental disomy of the entire X chromosome in a female with Duchenne muscular dystrophy. 898 59

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

X-linked recessive Emery-Dreifuss muscular dystrophy (EDMD) is an inherited muscle disorder characterized by the clinical triad of progressive wasting of humero-peroneal muscles, early contractures of the elbows, Achilles tendons and postcervical muscles, and cardiac conduction block with a high risk of sudden death. The gene for EDMD on Xq28 encodes a novel protein named emerin that localizes at the nuclear membrane of skeletal, cardiac and smooth muscles and some other non-muscle tissues. To investigate a possible physiological role for emerin, we examined the ultrastructural localization of the protein in human skeletal muscle and HeLa cells, using ultrathin cryosections. We found that the immune-labeled colloidal gold particles were localized on the nucleoplasmic surface of the inner nuclear membrane, but not on the nuclear pore. Emerin stayed on the cytoplasmic surface of the nuclear lamina, even after detergent treatment that solubilizes membrane lipids and washes out membrane proteins. These results suggest that emerin anchors at the inner nuclear membrane through the hydrophobic stretch, and protrudes from the hydrophilic region to the nucleoplasm where it interacts with the nuclear lamina. We speculate that emerin contributes to maintain the nuclear structure and stability, as well as nuclear functions, particularly in muscle tissues that have severe stress with rigorous contraction-relaxation movements and calcium flux.
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PMID:Emerin, deficiency of which causes Emery-Dreifuss muscular dystrophy, is localized at the inner nuclear membrane. 1073 16

Duchenne muscular dystrophy is an X-linked recessive disorder, primarily characterized by progressive muscle weakness and wasting. The disease results from the absence of dystrophin, however the precise molecular mechanisms leading to muscle pathology are poorly understood. Dystrophic muscles undergo increased oxidative stress and altered calcium homeostasis, which may contribute to myofiber loss by triggering both necrosis and apoptosis. Recent studies have identified ARC (apoptosis repressor with caspase recruitment domain) as an abundant protein in human muscle that can inhibit both hypoxia and caspase-8-induced apoptosis as well as protect cells from oxidative stress. To explore a potential role for ARC in protecting muscle fibers from dystrophic breakdown, we have cloned and characterized murine ARC and studied its expression in normal and dystrophic mouse muscle. ARC is expressed at high levels in striated muscle and displays fiber-type restricted expression patterns. ARC expression levels are normal in dystrophic mdx mice, although the intracellular localization pattern of ARC is slightly altered compared with normal muscles. Overexpression of ARC in transgenic mdx mice failed to alleviate the dystrophic pathology in skeletal muscles, suggesting that misregulation of the molecular pathways regulated by ARC does not significantly contribute to myofiber death.
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PMID:Characterization of ARC, apoptosis repressor interacting with CARD, in normal and dystrophin-deficient skeletal muscle. 1464 4

We reported three cases (two familial and one sporadic) of X-linked Emery-Dreifuss muscular dystrophy (EDMD), genetically documented. Two patients demonstrated a typical inclusion body myositis (IBM)-like morphology. The third patient had only minor changes. Patients had elbow and ankle contractures, progressive wasting of humeroperoneal muscles and cardiac failure (pacemaker implantation in all). There was a mutation within the Xq28 gene and complete absence of emerin in the nuclear membrane. Mononuclear cell infiltrations, rimmed vacuoles, amyloid deposits, as well as cytoplasmic and nuclear tubulofilamentous muscle inclusions were most unusual findings. Coexistence of IBM-like morphology and X-linked recessive EDMD might indicate that pathological features of IBM are nonspecific and may be present in other neuromuscular disorders.
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PMID:Coexistence of X-linked recessive Emery-Dreifuss muscular dystrophy with inclusion body myositis-like morphology. 1471 98

1. Duchenne muscular dystrophy (DMD) is a severe disease of skeletal muscle, characterized by an X-linked recessive inheritance and a lack of dystrophin in muscle fibres. It is associated with progressive and severe wasting and weakness of nearly all muscles and premature death by cardiorespiratory failure. 2. Studies investigating the susceptibility of dystrophic skeletal muscles to contraction-mediated damage, especially after lengthening actions where activated muscles are stretched forcibly, have concluded that dystrophin may confer protection to muscle fibres by providing a mechanical link between the contractile apparatus and the plasma membrane. In the absence of dystrophin, there is disruption to normal force transmission and greater stress placed upon myofibrillar and membrane proteins, leading to muscle damage. 3. Contraction protocols (involving activation and stretch of isolated muscles or muscle fibres) have been developed to assess the relative susceptibility of dystrophic (and otherwise healthy) muscles to contraction-induced injury. These protocols have been used successfully to determine the relative efficacy of different (gene, cell or pharmacological) interventions designed to ameliorate or cure the dystrophic pathology. More research is needed to develop specific 'contraction assays' that will assist in the evaluation of the clinical significance of different therapeutic strategies for muscular dystrophy.
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PMID:Role of contraction-induced injury in the mechanisms of muscle damage in muscular dystrophy. 1529 51


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