Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity

Ruggiero, Alessandra; Chen, Suet Nee; Lombardi, Raffaella; Rodrı́guez, Gabriela; Marian, Ali J.

doi:10.1093/cvr/cvs294

Cited by 38 publications

(39 citation statements)

References 28 publications

(43 reference statements)

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“…From these gene variants, we searched for those predicted to affect the function of the protein and presenting cardiac-specific expression, with the finding that FLNC-encoding the muscle-specific filamin C and implicated in myocyte differentiation-had a missense mutation in this patient (p.A1539T). This filamin is localized at the Z-discs of the sarcomere and interacts with other sarcomeric proteins, including myozenin-2 and myotilin 10,11 . To further evaluate the possibility that FLNC could be a novel gene associated with familial HCM, we next analysed whether the FLNC variant identified in this patient segregated with the disease in this family.…”

Section: Study Subjectsmentioning

confidence: 99%

Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy

et al. 2014

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Mutations in different genes encoding sarcomeric proteins are responsible for 50-60% of familial cases of hypertrophic cardiomyopathy (HCM); however, the genetic alterations causing the disease in one-third of patients are currently unknown. Here we describe a case with familial HCM of unknown cause. Whole-exome sequencing reveals a variant in the gene encoding the sarcomeric protein filamin C (p.A1539T) that segregates with the disease in this family. Sequencing of 92 HCM cases identifies seven additional variants segregating with the disease in eight families. Patients with FLNC mutations show marked sarcomeric abnormalities in cardiac muscle, and functional analysis reveals that expression of these FLNC variants resulted in the formation of large filamin C aggregates. Clinical studies indicate that FLNC-mutated patients have higher incidence of sudden cardiac death. On the basis of these findings, we conclude that mutations in the gene encoding the sarcomeric protein filamin C cause a new form of familial HMC.

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Section: Study Subjectsmentioning

confidence: 99%

Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy

et al. 2014

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“…, как основного модулятора сокращения и релаксации миоцитов, может активировать гипертрофию и дис-функцию миокарда, подверженного стрессовому воз- [6,13,18]. В некоторых случаях функциональные исследования вновь обнаруженных вариантов последовательности аминокислотных остатков означают, что они нарушают взаимодействие в цепи "протеин-протеин".…”

Section: +unclassified

Hypertrophic Cardiomyopathy: Genetic Alterations, Pathogenesis and Pathophysiology

Ватутин¹,

Тарадин²,

Maron

2014

Russ J Cardiol

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Настоящий обзор посвящен описанию генетических изменений, патогенети-ческих механизмов и патофизиологии гипертрофической кардиомиопатии на основе анализа последних опубликованных данных. Приведены современ-ные данные о роли выявленных многочисленных мутаций структурных, сокра-тительных и регуляторных белков саркомера в патогенезе кардиомиопатии. Освещены основные гипотезы патогенетического процесса, особое внимание уделено нарушению регуляции обмена кальция. Подчеркнута важность прове-дения генетического тестирования у больных гипертрофической кардиомио-патией и их родственников. В обзоре обсуждаются основные патофизиологические характеристики забо-левания с позиции их диагностической, клинической и прогностической зна-чимости. Кроме описания патофизиологических особенностей, в частности, обструкции выносящего тракта левого желудочка, диастолической дисфунк-ции, ишемии миокарда и нарушений ритма сердца, подчеркнута взаимосвязь этих нарушений с клинической картиной, а также роль современных методов исследования (позитронно-эмиссионная и компьютерная томография) в ран-ней диагностике и мониторировании клинического течения заболевания. Российский кардиологический журнал 2014, 5 (109): 35-42Ключевые слова: гипертрофическая кардиомиопатия, генетические мута-ции, патогенез, патофизиология. The review is dedicated to the description of genetic alterations, pathogenetic mechanisms and pathophysiology of hypertrophic cardiomyopathy, based on the analysis of current up to date information. A contemporary data is provided on the role a plenty discovered mutations of structural, contractile and regulatory sarcomere proteins in cardiomyopathy. The main hypotheses of pathogenetic processes are highlighted, especially the disordered calcium exchange. The importance of genetic testing of patients with hypertrophic cardiomyopathy and their relatives is underlined. The review concerns the basic pathophysiologic characteristics of the disease according to their diagnostic, clinical and prognostic value. Except the description of pathophysiologic properties, as a matter of fact, the obstruction of outflow in the left ventricle, diastolic dysfunction, myocardial ischemia and rhythm disorders, the connection of these conditions is underlined to clinical picture, and the role of contemporary instrumental diagnostic methods (positron-emission tomography, computed tomography) in early diagnostic and monitoring of the disease. Russ J Cardiol 2014, 5 (109): 35-42

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“…Potential pathways include altered calcium cycling and sarcomeric calcium sensitivity, disturbed biomechanical sensing, impaired energy homeostasis and impaired protein degradation [23 && , [25][26][27][28]; paracrine factors deriving from mutant cardiomyocytes may stimulate myocardial fibrosis [29].…”

Section: Cardiomyopathiesmentioning

confidence: 99%

“…Several mouse models recapitulating HCM phenotype have been generated [23 && , [28][29][30]. Studies in animal models revealed that various pharmacologic agents can prevent or reverse HCM phenotype [30][31][32][33][34][35][36].…”

Section: Cardiomyopathiesmentioning

confidence: 99%

Genetics and sudden death

Lombardi¹

2013

Current Opinion in Cardiology

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Advances in genetic sequencing technology are expected to significantly impact the clinical practice in the near future. Genetic testing represents a powerful tool for cause determination of arrhythmogenic cardiac diseases, efficient screening of family members, possible risk stratification and treatment choices. However, specific expertise is required for rational ordering and correct interpretation of the genetic screening results.

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Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity

Abstract: Thus, the cardiac phenotype in HCM caused by MYOZ2 mutations might be independent of calcineurin activity in the heart. Z disk abnormalities might provide the stimulus for the induction of cardiac hypertrophy caused by MYOZ2 mutations.

Cited by 38 publications

References 28 publications

Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy

Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy

Hypertrophic Cardiomyopathy: Genetic Alterations, Pathogenesis and Pathophysiology

Genetics and sudden death

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