A novel c.563 T>G, p.L189R lamin A/C mutation in identical twins with dilated cardiomyopathy.
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ABSTRACT:
SUBMITTER: Lee E
PROVIDER: S-EPMC5214720 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
Publications
A novel c.563 T>G, p.L189R lamin A/C mutation in identical twins with dilated cardiomyopathy.
Lee Euijae E Park Kyung-Taek KT Kang Jinwoo J Park Hyunkyung H Park Jin Joo JJ Oh Il-Young IY Yoon Yeonyee E YE
The Korean journal of internal medicine 20160308 1
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Project description:BackgroundHypertrophic cardiomyopathy in identical twins is rare. Cases of hypertrophic cardiomyopathy with homogenous and heterogeneous phenotypes have been described in the literature.Case summaryWe report a pair of monozygotic twins (Twin A and Twin B) with identical morphological expression of hypertrophic cardiomyopathy. On initial evaluation, both twins had resting left ventricular outflow tract obstruction, Grade II diastolic dysfunction, and New York Heart Association (NYHA) Class II symptoms, but they had a different clinical course afterward. Twin A progressed from NYHA Class II to Class III with a high left ventricular outflow tract pressure gradient that was unresponsive to medical treatment and required alcohol septal ablation. Twin B responded very well to medical treatment. Both patients had no risk factors for sudden cardiac death, and neither required an implantable cardioverter defibrillator.DiscussionThe morphology of hypertrophic cardiomyopathy has a strong genetic basis, but epigenetic factors may affect disease expression.
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Project description:We previously interrogated the transcriptome in heart tissue from Lmna(H222P/H222P) mice, a mouse model of cardiomyopathy caused by lamin A/C gene (LMNA) mutation, and found that the extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase branches of the mitogen-activated protein (MAP) kinase signaling pathway were abnormally hyperactivated prior to the onset of significant cardiac impairment. We have now used an alternative gene expression analysis tool to reanalyze this transcriptome and identify hyperactivation of a third branch of the MAP kinase cascade, p38? signaling. Biochemical analysis of hearts from Lmna(H222P/H222P) mice showed enhanced p38? activation prior to and after the onset of heart disease as well as in hearts from human subjects with cardiomyopathy caused by LMNA mutations. Treatment of Lmna(H222P/H222P) mice with the p38? inhibitor ARRY-371797 prevented left ventricular dilatation and deterioration of fractional shortening compared with placebo-treated mice but did not block the expression of collagen genes involved in cardiac fibrosis. These results demonstrate that three different branches of the MAP kinase signaling pathway with overlapping consequences are involved in the pathogenesis of cardiomyopathy caused by LMNA mutations. They further suggest that pharmacological inhibition of p38? may be useful in the treatment of this disease.
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Project description:BackgroundMutations in the gene encoding the nuclear membrane protein lamin A/C have been associated with at least 7 distinct diseases including autosomal dominant dilated cardiomyopathy with conduction system disease, autosomal dominant and recessive Emery Dreifuss Muscular Dystrophy, limb girdle muscular dystrophy type 1B, autosomal recessive type 2 Charcot Marie Tooth, mandibuloacral dysplasia, familial partial lipodystrophy and Hutchinson-Gilford progeria.MethodsWe used mutation detection to evaluate the lamin A/C gene in a 45 year-old woman with familial dilated cardiomyopathy and conduction system disease whose family has been well characterized for this phenotype 1.ResultsDNA from the proband was analyzed, and a novel 2 base-pair deletion c.908_909delCT in LMNA was identified.ConclusionsMutations in the gene encoding lamin A/C can lead to significant cardiac conduction system disease that can be successfully treated with pacemakers and/or defibrillators. Genetic screening can help assess risk for arrhythmia and need for device implantation.
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