Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myotonic dystrophy (DM) is an inherited multisystem disorder characterized by the presence of a high polymorphic expansion of trinucleotide (CTG) repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene. However, the role of myotonic dystrophy protein kinase (DMPK) has yet to be elucidated. Studies aimed to discover possible physiological targets of DMPK indicated several subcellular localization sites, such as neuromuscular junctions, myotendinous junctions, and terminal cisternae of the sarcoplasmic reticulum in the skeletal muscle and intercalated discs in the cardiac muscle. Here, we extend our previous observations on the localization of DMPK at gap junction (GJ) level in the heart, taking advantage of the polyclonal peptide-specific anti-DMPK antibodies raised against two different domains of the protein. DMPK was detected by immunofluorescence at the intercalated disc level by both antibodies. Double immunofluorescence staining experiments performed with each anti-DMPK and anti-connexin43 showed colocalization of the two antigens. Immunoblot analysis of partially purified GJs showed co-sedimentation of DMPK and connexin43. We conclude that GJs are a genuine localization site of DMPK. Given the known regulation exerted by protein kinases on assembly, trafficking, gating, and disassembly of connexins, such a localization may be relevant to the functional role of connexins. DM is the most common muscular dystrophy in adults, and is known by the cardiac involvement that is a common feature in DM patients. Localization of DMPK at GJ in relation to DM is also briefly discussed.
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PMID:Myotonic dystrophy protein kinase of the cardiac muscle: evaluation using an immunochemical approach. 1222 10

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, is a clinically and genetically heterogeneous neuromuscular disorder. DM is characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multisystem involvement. Type 1 DM (DM1) is caused by a (CTG)(n) expansion in the 3' untranslated region of DMPK in 19q13.3. Multiple families, predominantly of German descent and with clinically variable presentation that included proximal myotonic myopathy (PROMM) and type 2 DM (DM2) but without the DM1 mutation, showed linkage to the 3q21 region and were recently shown to segregate a (CCTG)(n) expansion mutation in intron 1 of ZNF9. Here, we present linkage to 3q21 and mutational confirmation in 17 kindreds of European origin with PROMM and proximal myotonic dystrophy, from geographically distinct populations. All patients have the DM2 (CCTG)(n) expansion. To study the evolution of this mutation, we constructed a comprehensive physical map of the DM2 region around ZNF9. High-resolution haplotype analysis of disease chromosomes with five microsatellite and 22 single-nucleotide polymorphism markers around the DM2 mutation identified extensive linkage disequilibrium and a single shared haplotype of at least 132 kb among patients from the different populations. With the exception of the (CCTG)(n) expansion, the available markers indicate that the DM2 haplotype is identical to the most common haplotype in normal individuals. This situation is reminiscent of that seen in DM1. Taken together, these data suggest a single founding mutation in DM2 patients of European origin. We estimate the age of the founding haplotype and of the DM2 (CCTG) expansion mutation to be approximately 200-540 generations.
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PMID:Confirmation of the type 2 myotonic dystrophy (CCTG)n expansion mutation in patients with proximal myotonic myopathy/proximal myotonic dystrophy of different European origins: a single shared haplotype indicates an ancestral founder effect. 1297 Aug 45

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19 (DM1) or 3 (DM2). In 2001, we demonstrated that DM2 is caused by a CCTG expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene. To investigate the ancestral origins of the DM2 expansion, we compared haplotypes for 71 families with genetically confirmed DM2, using 19 short tandem repeat markers that we developed that flank the repeat tract. All of the families are white, with the majority of Northern European/German descent and a single family from Afghanistan. Several conserved haplotypes spanning >700 kb appear to converge into a single haplotype near the repeat tract. The common interval that is shared by all families with DM2 immediately flanks the repeat, extending up to 216 kb telomeric and 119 kb centromeric of the CCTG expansion. The DM2 repeat tract contains the complex repeat motif (TG)(n)(TCTG)(n)(CCTG)(n). The CCTG portion of the repeat tract is interrupted on normal alleles, but, as in other expansion disorders, these interruptions are lost on affected alleles. We examined haplotypes of 228 control chromosomes and identified a potential premutation allele with an uninterrupted (CCTG)(20) on a haplotype that was identical to the most common affected haplotype. Our data suggest that the predominant Northern European ancestry of families with DM2 resulted from a common founder and that the loss of interruptions within the CCTG portion of the repeat tract may predispose alleles to further expansion. To gain insight into possible function of the repeat tract, we looked for evolutionary conservation. The complex repeat motif and flanking sequences within intron 1 are conserved among human, chimpanzee, gorilla, mouse, and rat, suggesting a conserved biological function.
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PMID:Myotonic dystrophy type 2: human founder haplotype and evolutionary conservation of the repeat tract. 1450 73

Creatine monohydrate (CrM) supplementation may increase strength in some types of muscular dystrophy. A recent study in myotonic muscular dystrophy type 1 (DM1) did not find a significant treatment effect, but measurements of muscle phosphocreatine (PCr) were not performed. We completed a randomized, double-blind, cross-over trial using 34 genetically confirmed adult DM1 patients without significant cognitive impairment. Participants received CrM (5 g, approximately 0.074 g/kg daily) and a placebo for each 4-month phase with a 6-week wash-out. Spirometry, manual muscle testing, quantitative isometric strength testing of handgrip, foot dorsiflexion, and knee extension, handgrip and foot dorsiflexion endurance, functional tasks, activity of daily living scales, body composition (total, bone, and fat-free mass), serum creatine kinase activity, serum creatinine concentration and clearance, and liver function tests were completed before and after each intervention, and muscle PCr/beta-adenosine triphosphate (ATP) ratios of the forearm flexor muscles were completed at the end of each phase. CrM supplementation did not increase any of the outcome measurements except for plasma creatinine concentration (but not creatinine clearance). Thus, CrM supplementation at 5 g daily does not have any effects on muscle strength, body composition, or activities of daily living in patients with DM1, perhaps because of a failure of the supplementation to increase muscle PCr/beta-ATP content.
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PMID:Creatine monohydrate supplementation does not increase muscle strength, lean body mass, or muscle phosphocreatine in patients with myotonic dystrophy type 1. 1469 98

Accumulation of RNA CUG repeats in myotonic dystrophy type 1 (DM1) patients leads to the induction of a CUG-binding protein, CUGBP1, which increases translation of several proteins that are required for myogenesis. In this paper, we examine the role of overexpression of CUGBP1 in DM1 muscle pathology using transgenic mice that overexpress CUGBP1 in skeletal muscle. Our data demonstrate that the elevation of CUGBP1 in skeletal muscle causes overexpression of MEF2A and p21 to levels that are significantly higher than those in skeletal muscle of wild type animals. A similar induction of these proteins is observed in skeletal muscle of DM1 patients with increased levels of CUGBP1. Immunohistological analysis showed that the skeletal muscle from mice overexpressing CUGBP1 is characterized by a developmental delay, muscular dystrophy, and myofiber-type switch: increase of slow/oxidative fibers and the reduction of fast fibers. Examination of molecular mechanisms by which CUGBP1 up-regulates MEF2A shows that CUGBP1 increases translation of MEF2A via direct interaction with GCN repeats located within MEF2A mRNA. Our data suggest that CUGBP1-mediated overexpression of MEF2A and p21 inhibits myogenesis and contributes to the development of muscle deficiency in DM1 patients.
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PMID:Overexpression of CUG triplet repeat-binding protein, CUGBP1, in mice inhibits myogenesis. 1472 59

Myotonic dystrophy (DM)--the most common form of muscular dystrophy in adults, affecting 1/8000 individuals--is a dominantly inherited disorder with a peculiar and rare pattern of multisystemic clinical features affecting skeletal muscle, the heart, the eye, and the endocrine system. Two genetic loci have been associated with the DM phenotype: DM1, on chromosome 19, and DM2, on chromosome 3. In 1992, the mutation responsible for DM1 was identified as a CTG expansion located in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). How this untranslated CTG expansion causes myotonic dystrophy type 1(DM1) has been controversial. The recent discovery that myotonic dystrophy type 2 (DM2) is caused by an untranslated CCTG expansion, along with other discoveries on DM1 pathogenesis, indicate that the clinical features common to both diseases are caused by a gain-of-function RNA mechanism in which the CUG and CCUG repeats alter cellular function, including alternative splicing of various genes. We discuss the pathogenic mechanisms that have been proposed for the myotonic dystrophies, the clinical and molecular features of DM1 and DM2, and the characterization of murine and cell-culture models that have been generated to better understand these diseases.
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PMID:Myotonic dystrophy: RNA pathogenesis comes into focus. 1506 17

Myotonic dystrophy (dystrophia myotonica, DM) is the most common form of muscular dystrophy in adults. The presence of two genetic forms of this complex multisystemic disease (DM1 and DM2) was unrecognized until the genetic cause of DM1 was identified in 1992. The fact that the DM1 mutation is an untranslated CTG expansion led to extended controversy about the molecular pathophysiology of this disease. When the DM2 mutation was identified in 2001 as being a similarly untranslated CCTG expansion, the molecular and clinical parallels between DM1 and DM2 substantiated the role of a novel mechanism in generating the unusual constellation of clinical features seen in these diseases: the repeat expansions expressed at the RNA level alter RNA processing, at least in part by interfering with alternative splicing of other genes. For example, in both DM1 and DM2, altered splicing of chloride channel and insulin receptor transcripts leads to myotonia and insulin resistance, respectively. Although other mechanisms may underlie the differences between DM1 and DM2, the pathogenic effects of the RNA mechanism are now clear, which will facilitate development of appropriate treatments.
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PMID:RNA pathogenesis of the myotonic dystrophies. 1563 15

Type 1 myotonic dystrophy or DM1 (Steinert's disease), which is the commonest muscular dystrophy in adults, has intrigued physicians for over a century. Unusual features, compared with other dystrophies, include myotonia, anticipation, and involvement of other organs, notably the brain, eyes, smooth muscle, cardiac conduction apparatus, and endocrine system. Morbidity is high, with a substantial mortality relating to cardiorespiratory dysfunction. More recently a second form of multisystem myotonic disorder has been recognized and variously designated as proximal myotonic myopathy (PROMM), proximal myotonic dystrophy (PDM), or DM2. For both DM1 and DM2 the molecular basis is expansion of an unstable repeat sequence in a noncoding part of a gene (DMPK in DM1 and ZNF9 in DM2). There is accumulating evidence that the basic molecular mechanism is disruption of mRNA metabolism, which has far-reaching effects on many other genes, in part through the induction of aberrant splicing, explaining the multisystemic nature of the disease. The unstable nature of the expansion provides a molecular explanation for anticipation. This review emphasizes the clinical similarities and differences between DM1 and DM2. It examines current views about the molecular basis of these disorders, and contrasts them with other repeat expansion disorders that have increasingly been recognized as a cause of neurological disease.
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PMID:Clinical and molecular aspects of the myotonic dystrophies: a review. 1577 Jun 60

Myotonic dystrophy(DM), the most common form of adult-onset muscular dystrophy, comprises at least 2 sub-types, DM1 and DM2. DM1 is caused by the expansion of a CTG repeat located in the 3' untranslated region (3UTR) of the DM protein kinase (DMPK) gene. Recently, the expansion of a CCTG tetranucleotide repeat located in the first intron of the ZNF9 gene was identified as the mutation responsible for DM2. Since both DM1 and DM2 are caused by the expansion of repetitive sequences, some common factors that interact with these sequences might be involved in the pathogenesis of DM. MBNL (muscleblind) 1 is a candidate for such factors and is thought to be sequestered by the expanded forms of DM transcripts.
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PMID:[Molecular pathways to myotonic dystrophy]. 1577 54

Patients with muscular dystrophy may be prone to nutrient deficiency due to mobility limitations or oropharyngeal weakness. Patients with myotonic muscular dystrophy (DM1) may be particularly prone to nutritional deficiencies from associated dysmotility of the entire gastrointestinal tract. We prospectively evaluated nutritional intake, body composition, and muscle strength in adult patients with DM1 (n = 29) and other muscular dystrophies (n = 22) on two occasions separated by approximately 6 months. Handgrip was significantly lower and knee extension higher for DM1 compared to other dystrophies, with no between-group differences in nutritional intakes. Many patients in both groups demonstrated inadequate nutrient intake of protein, energy, vitamins (water and fat soluble), and minerals (calcium and magnesium). Significant correlations were found between measures of strength and certain individual nutrients (e.g., copper and water-soluble vitamins). These data indicate that a substantial number of adults with muscular dystrophy do not meet current dietary intake recommendations. The potential clinical implications of these findings are discussed.
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PMID:Nutritional inadequacy in adults with muscular dystrophy. 1578 16


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