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 (MD), an autosomal dominant multisystemic disorder with a high phenotypic variability, is the most common muscular dystrophy in adult life. The mutation underlying DM has been characterized as an expanded CTG trinucleotide repeat sequence in the 3 untranslated region of a protein kinase gene on chromosome 19q13.2-13.3. We have analyzed the presence of CTG intergenerational variations on transmission in parent-child pairs affected with DM. The series includes 90% of all living affected descendants (symptomatic or asymptomatic) from a given myotonic dystrophy (DM) patient. A contraction of the CTG repeat size was observed in ten parent-child pairs (14.1%) and remained unchanged in five (7%) pairs. The number of CTG repeats decreased in 2/30 maternal transmissions (6.7%) and in 8/41 paternal transmissions (19.5%). We found 14 asymptomatic individuals carrying the CTG expansion among the offspring. In six of them, a contraction of the CTG repeat was observed, and in all six cases, the DM allele was paternally transmitted. Since nearly all the asymptomatic family members of DM patients were analyzed in this series, the observed percentage of contractions can be considered more realistic, even though the number of parent-child pairs is small.
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PMID:Frequency of intergenerational contractions of the CTG repeats in myotonic dystrophy. 890 94

Myotonic dystrophy is a dominantly inherited clinically variable multisystemic disorder, and has been found to be caused by heterozygosity for a trinucleotide repeat expansion mutation in the 3' untranslated region of a protein kinase gene (DM kinase). The mechanisms by which the expanded repeat in DNA results in a dominant biochemical defect and the varied clinical phenotype, is not known. We have recently proposed a model where disease pathogenesis may occur at the RNA level in myotonic dystrophy: the mutant DM kinase RNA with the expansion mutation may disrupt cellular RNA metabolism in some general manner, as evidenced by defects in RNA processing of the normal DM kinase gene in heterozygous patients (dominant negative RNA mutation). Here we further test this hypothesis by measuring RNA metabolism of other genes in patient muscle biopsies (nine adult onset myotonic dystrophy patients, two congenital muscular dystrophy patients, four normal controls, and four myopathic controls). We focused on the insulin receptor gene because of the documented insulin resistance of DM patients. We show that there is a significant decrease in insulin receptor RNA in both total RNA and RNA polyA+ pools relative to normal and myopathic control muscles (P < 0.002), measured relative to both dystrophin RNA and muscle sodium channel RNA. We also show reductions in insulin receptor protein. Our results reinforce the concept of a generalized RNA metabolism defect in myotonic dystrophy, and offer a possible molecular mechanism for the increased insulin resistance observed in many myotonic dystrophy patients.
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PMID:RNA metabolism in myotonic dystrophy: patient muscle shows decreased insulin receptor RNA and protein consistent with abnormal insulin resistance. 912 13

Myotonic dystrophy (DM) is the most common form of adult onset muscular dystrophy, with an incidence of approximately 1 in 8500 adults. DM is caused by an expanded number of trinucleotide repeats in the 3'-untranslated region (UTR) of a cAMP-dependent protein kinase (DM protein kinase, DMPK). Although a large number of transgenic animals have been generated with different gene constructions and knock-outs, none of them faithfully recapitulates the multisystemic and often severe phenotype seen in human patients. The transgenic data suggest that myotonic dystrophy is not caused simply by a biochemical deficiency or abnormality in the DM kinase gene product. Emerging studies suggest that two novel pathogenetic mechanisms may play a role in the disease: the expanded repeats appear to cause haploinsufficiency of a neighboring homeobox gene and also abnormal DMPK RNA appears to have a detrimental effect on RNA homeostasis. The complex, multisystemic phenotype may reflect an underlying multifaceted molecular pathophysiology: the facial dysmorphology may be due to pattern defects caused by haploinsufficiency of the homeobox gene, while the muscle disease and endocrine abnormalities may be due to both altered RNA metabolism and deficiency of the cAMP DMPK protein.
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PMID:Myotonic dystrophy: molecular windows on a complex etiology. 949 Jul 78

The genetic abnormality in myotonic muscular dystrophy, multiple CTG repeats lie upstream of a gene that encodes a novel protein kinase, myotonic dystrophy protein kinase (DMPK). Phospholemman (PLM), a major membrane substrate for phosphorylation by protein kinases A and C, induces Cl currents (I(Cl(PLM))) when expressed in Xenopus oocytes. To test the idea that PLM is a substrate for DMPK, we measured in vitro phosphorylation of purified PLM by DMPK. To assess the functional effects of PLM phosphorylation we compared I(Cl(PLM)) in Xenopus oocytes expressing PLM alone to currents in oocytes co-expressing DMPK, and examined the effect of DMPK on oocyte membrane PLM expression. We found that PLM is indeed a good substrate for DMPK in vitro. Co-expression of DMPK with PLM in oocytes resulted in a reduction in I(Cl(PLM)). This was most likely a specific effect of phosphorylation of PLM by DMPK, as the effect was not present in oocytes expressing a phos(-) PLM mutant in which all potential phosphorylation had been disabled by Ser --> Ala substitution. The biophysical characteristics of I(Cl(PLM)) were not changed by DMPK or by the phos(-) mutation. Co-expression of DMPK reduced the expression of PLM in oocyte membranes, suggesting a possible mechanism for the observed reduction in I(Cl(PLM)) amplitude. These data show that PLM is a substrate for phosphorylation by DMPK and provide functional evidence for modulation of PLM function by phosphorylation.
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PMID:Phospholemman is a substrate for myotonic dystrophy protein kinase. 1081 36

Myotonic dystrophy, a progressive autosomal dominant disorder, is associated with an expansion of a CTG repeat tract located in the 3'-untranslated region of a serine/threonine protein kinase, DMPK. DMPK modulates skeletal muscle Na channels in vitro, and thus we hypothesized that mice deficient in DMPK would have altered muscle Na channel gating. We measured macroscopic and single channel Na currents from cell-attached patches of skeletal myocytes from mice heterozygous (DMPK(+/-)) and homozygous (DMPK(-/-)) for DMPK loss. In DMPK(-/-) myocytes, Na current amplitude was reduced because of reduced channel number. Single channel recordings revealed Na channel reopenings, similar to the gating abnormality of human myotonic muscular dystrophy (DM), which resulted in a plateau of Na current. The gating abnormality deteriorated with increasing age. In DMPK(+/-) muscle there was reduced Na current amplitude and increased Na channel reopenings identical to those in DMPK(-/-) muscle. Thus, these mouse models of complete and partial DMPK deficiency reproduce the Na channel abnormality of the human disease, providing direct evidence that DMPK deficiency underlies the Na channel abnormality in DM.
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PMID:Skeletal muscle sodium channel gating in mice deficient in myotonic dystrophy protein kinase. 1100 35

Myotonic muscular dystrophy is the most frequent autosomal muscular dystrophy affecting adults and children. It affects multiple organ systems and is probably the best example of variable expressivity in a human disease. This article presents a patient with congenital myotonic dystrophy who had facial dysmorphism, hypotonia, talipes, feeding and respiratory difficulties in the neonatal period and later presented to us with developmental delay and had percussion myotonia. His mother had clinical and electrophysiological features of myotonia. Expansion of unstable CTG trinucleotide repeat in the myotonic protein kinase gene was demonstrated in both. The identification of this molecular defect allows its specific diagnosis in relation to other neuromuscular disorders as well as accurate prenatal diagnosis.
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PMID:Congenital myotonic dystrophy. 1140 62

Myotonic dystrophy (DM1) is the most common form of adult muscular dystrophy and is inherited as an autosomal dominant trait. The genetic basis of DM1 is the expansion of a CTG repeat in the 3' untranslated region of a protein kinase gene (DMPK). The molecular mechanism by which this expanded repeat produces the pathophysiology of DM1 remains unknown. Transcripts from the expanded allele accumulate as foci in the nucleus of DM1 cells and it has been suggested that these transcript foci sequester cellular proteins that are required for normal nuclear function. We have investigated the role of three RNA-binding proteins, CUG-BP, hnRNP C and MBNL, as possible sequestered factors. Using a combination of indirect immunofluorescence to detect endogenous proteins and overexpression of proteins with green fluorescent protein (GFP) tags we have shown that CUG-BP and hnRNP C do not co-localise with expanded repeat foci in DM1 cell lines. However, GFP-tagged MBNL does itself form foci in DM1 cell lines and co-localises with the foci of expanded repeat transcripts. GFP-tagged MBNL does not appear as foci in non-DM1 cell lines. This work provides further support for the involvement of MBNL in DM1.
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PMID:In vivo co-localisation of MBNL protein with DMPK expanded-repeat transcripts. 1143 21

Myotonic dystrophy (DM1) is the most common form of adult muscular dystrophy with an estimated incidence of 1/8000 births. The mutation responsible for this condition is an expanded CTG repeat within the 3' untranslated region of the protein kinase gene DMPK. Strong nucleosome positioning signals created by this expanded repeat cause a reduction in gene expression within the region. This "field effect" is further confounded by the retention of DMPK expansion containing transcripts, which acquire a toxic gain of function. Thus, the various manifestations exhibited by DM1 patients can be explained as a result of gene silencing, nuclear retention and sequestration of nuclear factors by the CUG containing transcript.
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PMID:Myotonic dystrophy--a multigene disorder. 1171 77

Dystroglycan is a component of the dystrophin-glycoprotein complex (DGC) in muscle and a cell surface receptor for laminin. Numerous muscular dystrophies are the result of disruption of proteins comprising the DGC, but the underlying pathogenetic mechanisms are unknown. Because apoptosis is an early feature of muscular dystrophy in vivo, and perturbation of cell-extracellular matrix associations is known to induce apoptosis, we investigated the role of dystroglycan-laminin interactions in the propagation and maintenance of cell survival signals in muscle cells. We found that disrupting the interaction between alpha-dystroglycan and the extracellular matrix protein laminin induces apoptosis in muscle cells. This increase in apoptosis is mediated in part by caspase activation and can be blocked by a caspase-3 inhibitor. We demonstrate a role for the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in muscle cell-survival signaling using a pharmacological inhibitor of PI3K. Treatment with this inhibitor resulted in decreased phosphorylation of AKT and its downstream effector glycogen synthase kinase (GSK)-3beta and induced apoptosis in muscle cell cultures. Disruption of dystroglycan-laminin interactions resulted in decreased phosphorylation of AKT and GSK-3beta. Furthermore, activation of AKT prior to the disruption of dystroglycan-laminin protected the muscle cells from the induction of apoptosis. These results support a role for the PI3K/AKT pathway in the propagation of cell-survival signals mediated by the DGC and provide new insight into the molecular pathogenesis associated with the development of muscular dystrophies.
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PMID:Inhibition of dystroglycan binding to laminin disrupts the PI3K/AKT pathway and survival signaling in muscle cells. 1240 86

Nonsense-mediated mRNA decay (NMD) is an mRNA quality-control mechanism that degrades aberrant mRNAs containing premature translation termination codons (PTCs). The essential proteins for NMD include SMG-1, a protein kinase, and Upf1, a substrate of SMG-1 with RNA helicase activity. In this study, we evaluated the effects of NMD inhibition by siRNA-mediated knockdown of SMG-1 or Upf1 on the phenotype of Ullrich disease, an autosomal recessive congenital muscular dystrophy. The patient studied showed a homozygous frameshift mutation with a PTC in the collagen VI alpha2 gene, which encodes a truncated but partially functional protein. The patient's fibroblasts showed a nearly complete loss of the triple-helical collagen VI protein and functional defects in the extracellular matrix (ECM) due to the crucial deficiency of the collagen VI alpha2 protein. We have shown that siRNA-mediated knockdown of SMG-1 or Upf1 causes the up-regulation of the mutant triple-helical collagen VI, resulting in the formation of partially functional ECM. We suggest that the inhibition of NMD may be useful as a therapeutic approach to treat some human genetic diseases exacerbated by NMD.
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PMID:Specific inhibition of nonsense-mediated mRNA decay components, SMG-1 or Upf1, rescues the phenotype of Ullrich disease fibroblasts. 1680 16


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