Cardiac Involvement in a Large Kindred With Myotonic Dystrophy

Tokgözoğlu, Lâle

doi:10.1001/jama.1995.03530100053034

Cited by 53 publications

(37 citation statements)

References 50 publications

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“…Concurrently Mbnl1 depletion results in the enhanced expression of embryonic splice isoforms of RNAs regulating sodium and calcium currents ( Scn5a, Asph, Junctin, Junctate, Atp2a1, Atp11a, Cacna1s, Ryr2 ), intra and inter cellular transport ( Clta, Stx2 and Tjp1/Zo-1 ), compliance of the myocardium ( Myom1 ), cell survival ( Capn3, Sirt2, Csda ) cytoskeleton and sarcomere assembly and function ( Trim55 , Mapt , Pdlim3 , Pdlim5 , Sorbs1 , Sorbs2 , Fhod1 and Spag9 ) and encoding sarcomere structural proteins ( Tnnt2, Ldb3 ). As several of these features are observed in DM112345678910111232344973, this study supports a key role for Mbnl1 depletion in the initiation of DM1 cardiac pathology.…”

Section: Discussionsupporting

confidence: 79%

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Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms

Dixon

Choi

El‐Ghazali

et al. 2015

Sci Rep

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Cardiac dysfunction is a prominent cause of mortality in myotonic dystrophy I (DM1), a disease where expanded CUG repeats bind and disable the muscleblind-like family of splice regulators. Deletion of muscleblind-like 1 (Mbnl1ΔE2/ΔE2) in 129 sv mice results in QRS, QTc widening, bundle block and STc narrowing at 2–4 months of age. With time, cardiac function deteriorates further and at 6 months, decreased R wave amplitudes, sinus node dysfunction, cardiac hypertrophy, interstitial fibrosis, multi-focal myocardial fiber death and calcification manifest. Sudden death, where no end point illness is overt, is observed at a median age of 6.5 and 4.8 months in ~67% and ~86% of male and female Mbnl1ΔE2/ΔE2 mice, respectively. Mbnl1 depletion results in the persistence of embryonic splice isoforms in a network of cardiac RNAs, some of which have been previously implicated in DM1, regulating sodium and calcium currents, Scn5a, Junctin, Junctate, Atp2a1, Atp11a, Cacna1s, Ryr2, intra and inter cellular transport, Clta, Stx2, Tjp1, cell survival, Capn3, Sirt2, Csda, sarcomere and cytoskeleton organization and function, Trim55, Mapt, Pdlim3, Pdlim5, Sorbs1, Sorbs2, Fhod1, Spag9 and structural components of the sarcomere, Myom1, Tnnt2, Zasp. Thus this study supports a key role for Mbnl1 loss in the initiation of DM1 cardiac disease.

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Section: Discussionsupporting

confidence: 79%

“…Poor R wave progression is also a feature noted in DM16. Left ventricular hypertrophy, dilation and systole dysfunction occur less frequently and can manifest in the absence conduction disorders1278910. Histopathological changes include multi focal myofibrillar loss, fatty infiltration and fibrosis12610.…”

mentioning

confidence: 99%

Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms

Dixon

Choi

El‐Ghazali

et al. 2015

Sci Rep

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“…Conduction system defects and arrhythmias are the major abnormalities. Myocardial dysfunction, ischemic heart disease, and mitral valve prolapse are observed less frequently 10,11,14,15,24,25…”

Section: Discussionmentioning

confidence: 99%

“…DM1 is caused by an unstable expansion of a cytosine-thymine-guanine (CTG) repeat in the dystrophia myotonica phosphokinase gene on chromosome 19q13.3,5-7 with the CTG repeat size being correlated positively with the disease severity and inversely with the age at onset 8-11…”

Section: Introductionmentioning

confidence: 99%

Prolonged Corrected QT Interval in Patients with Myotonic Dystrophy Type 1

et al. 2013

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Background and PurposezzSudden cardiac death is one of the leading causes of death in patients with myotonic dystrophy type 1 (DM1). It has been proposed that a prolonged QT interval is associated with sudden cardiac death in several neurological diseases, including multiple system atrophy, idiopathic Parkinson's disease, and diabetic autonomic neuropathy. However, analyses of the corrected QT (QTc) interval in DM1 patients are rare in the literature. The purposes of this study were to determine the association between the QT interval and DM1, and the affecting factors.MethodszzThirty-nine patients diagnosed with DM1 through genetic testing were enrolled. The QTc interval (calculated using Bazett's formula: QTc=QT/√RR) was compared between these patients and 39 normal healthy controls. The clinical and laboratory factors affecting QTc interval in the patient group were investigated.ResultszzThe QTc interval was significantly longer in the DM1 group (411.2±44.7 msec, mean± SD) than in the normal control group (355.6±20.6 msec). Intragroup analysis revealed that a prolonged QTc interval in DM1 patients was associated with being female and older, having a longer disease duration, and exhibiting abnormal electrocardiography findings.ConclusionszzThe higher incidence of sudden cardiac death in the DM1 population is associated with the observed prolonged QTc interval in those patients.

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“…RNA toxicity is the cause of DM1 pathology, where transcripts containing expanded CUG repeats accumulate in the nucleus as discrete RNA foci 3 . The length of repeat expansion correlates with DM1 disease onset and severity 4,5 . Expanded CUG repeat RNA transcripts disrupt alternative RNA splicing mediated by muscleblind-like (MBNL) 6 and the CUG binding protein 1 (CUG-BP1) 7 RNA binding protein families, causing toxicity.…”

Section: Introductionmentioning

confidence: 99%

Identification of genes in toxicity pathways of trinucleotide-repeat RNA in C. elegans

Garcia

Tabach

Lourenco

et al. 2014

Nat Struct Mol Biol

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Myotonic dystrophy disorders are caused by expanded CUG repeats in non-coding regions. To reveal mechanisms of CUG repeat pathogenesis we used C. elegans expressing CUG repeats to identify gene inactivations that modulate CUG repeat toxicity. We identified 15 conserved genes that function as suppressors or enhancers of CUG repeat-induced toxicity and modulate formation of nuclear RNA foci by CUG repeats. These genes regulated CUG repeat-induced toxicity through distinct mechanisms including RNA export and RNA clearance, suggesting that CUG repeat toxicity is mediated by multiple pathways. A subset is shared with other degenerative disorders. The nonsense-mediated mRNA decay (NMD) pathway plays a conserved role regulating CUG repeat RNA transcript levels and toxicity, and NMD recognition of toxic RNAs depends on 3′UTR GC nucleotide content. Our studies suggest a broader surveillance role for NMD where variations in this pathway influence multiple degenerative diseases.

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Cardiac Involvement in a Large Kindred With Myotonic Dystrophy

Cited by 53 publications

References 50 publications

Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms

Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms

Prolonged Corrected QT Interval in Patients with Myotonic Dystrophy Type 1

Identification of genes in toxicity pathways of trinucleotide-repeat RNA in C. elegans

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