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 type 2 (DM2) is a common adult onset muscular dystrophy caused by a dominantly transmitted (CCTG)( n ) expansion in intron 1 of the CNBP gene. In DM2 there is no obvious evidence for an intergenerational increase of expansion size, and no congenital cases have been confirmed. We describe the clinical and histopathological features, and provide the genetic and molecular explanation for juvenile onset of myotonia in a 14-year-old female with DM2 and her affected mother presenting with a more severe phenotype despite a later onset of symptoms. Histological and immunohistochemical findings correlated with disease severity or age at onset in both patients. Southern blot on both muscle and blood samples revealed only a small increase in the CCTG repeat number through maternal transmission. Fluorescence in situ hybridization, in combination with MBNL1 immunofluorescence on muscle sections, showed the presence of mutant mRNA and MBNL1 in nuclear foci; the fluorescence intensity and its area appeared to be similar in the two patients. Splicing analysis of the INSR, CLCN1 and MBNL1 genes in muscle tissue demonstrates that the level of aberrant splicing isoforms was lower in the daughter than in the mother. However, in the CLCN1 gene, a heterozygous mutation c.501C>G p.F167L was present in the daughter's DNA and found to be maternally inherited. Biomolecular findings did not explain the unusual young onset in the daughter. The co-segregation of DM2 with a recessive CLCN1 mutation provided the explanation for the unusual clinical findings.
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PMID:Co-segregation of DM2 with a recessive CLCN1 mutation in juvenile onset of myotonic dystrophy type 2. 2240 75

Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy, caused by expansion of a CTG triplet repeat in the 3' untranslated region (3'UTR) of the myotonic dystrophy protein kinase (DMPK) gene. The pathological CTG repeats result in protein trapping by expanded transcripts, a decreased DMPK translation and the disruption of the chromatin structure, affecting neighboring genes expression. The muscleblind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) are two families of tissue-specific regulators of developmentally programmed alternative splicing that act as antagonist regulators of several pre-mRNA targets, including troponin 2 (TNNT2), insulin receptor (INSR), chloride channel 1 (CLCN1) and MBNL2. Sequestration of MBNL proteins and up-regulation of CELF1 are key to DM1 pathology, inducing a spliceopathy that leads to a developmental remodelling of the transcriptome due to an adult-to-foetal splicing switch, which results in the loss of cell function and viability. Moreover, recent studies indicate that additional pathogenic mechanisms may also contribute to disease pathology, including a misregulation of cellular mRNA translation, localization and stability. This review focuses on the cause and effects of MBNL and CELF1 deregulation in DM1, describing the molecular mechanisms underlying alternative splicing misregulation for a deeper understanding of DM1 complexity. To contribute to this analysis, we have prepared a comprehensive list of transcript alterations involved in DM1 pathogenesis, as well as other deregulated mRNA processing pathways implications.
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PMID:An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I. 3297 3