A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia

Dhandapany, Perundurai S.; Sadayappan, Sakthivel; Xue, Yali; Powell, Gareth T.; Rani, Deepa Selvi; Nallari, Prathiba; Singh, Taranjit; Khullar, Madhu; Soares, Pedro; Bahl, Ajay; Tharkan, Jagan Mohan; Vaideeswar, Pradeep; Rathinavel, Andiappan; Narasimhan, Calambur; Ayapati, Dharma Rakshak; Ayub, Qasim; Mehdi, S. Qasim; Oppenheimer, Stephen; Richards, Martin B.; Price, Alkes L.; Patterson, Nick; Reich, David; Singh, Lalji; Tyler‐Smith, Chris; Thangaraj, Kumarasamy

doi:10.1038/ng.309

Cited by 252 publications

(304 citation statements)

References 27 publications

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“…1B) that included 500 bp of a functional exon-intron-exon containing either the reference or variant sequence (Datasets S3 and S4). Using this assay we confirmed that a previously described MYBPC3 pathogenic HCM variant (12,13) significantly altered splicing in comparison with the reference sequence (P = 2.3e-06, two-sided Fisher's exact test, Dataset S6). Similarly, we demonstrated significantly altered splicing (P < 0.001, two-sided Fisher's exact test) in 14 of 57 LMNA splicing candidates (Dataset S5) and in 39 of 139 MYBPC3 splicing candidates ( Fig.…”

Section: Significancesupporting

confidence: 62%

Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing

Ito

Patel

Gorham

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Genetic variants that cause haploinsufficiency account for many autosomal dominant (AD) disorders. Gene-based diagnosis classifies variants that alter canonical splice signals as pathogenic, but due to imperfect understanding of RNA splice signals other variants that may create or eliminate splice sites are often clinically classified as variants of unknown significance (VUS). To improve recognition of pathogenic splice-altering variants in AD disorders, we used computational tools to prioritize VUS and developed a cell-based minigene splicing assay to confirm aberrant splicing. Using this two-step procedure we evaluated all rare variants in two AD cardiomyopathy genes, lamin A/C (LMNA) and myosin binding protein C (MYBPC3). We demonstrate that 13 LMNA and 35 MYBPC3 variants identified in cardiomyopathy patients alter RNA splicing, representing a 50% increase in the numbers of established damaging splice variants in these genes. Over half of these variants are annotated as VUS by clinical diagnostic laboratories. Familial analyses of one variant, a synonymous LMNA VUS, demonstrated segregation with cardiomyopathy affection status and altered cardiac LMNA splicing. Application of this strategy should improve diagnostic accuracy and variant classification in other haploinsufficient AD disorders.D NA sequence analysis of patient DNA has been used to clinically diagnose associated inherited diseases, leading to the identification of thousands of rare sequence variants in affected and unaffected individuals. Interpreting the medical significance of these variants has proven to be a significant challenge. The annotation of nonsense, frameshift, insertion, and deletion variants that cause a highly predictable outcome [i.e., loss of function (LoF) of proteins encoded by disease genes] allows these to be clinically classified as pathogenic variants in more than 4,000 genes that cause disease by haploinsufficiency (1). Classification of rare synonymous and missense variants in these genes, however, has been more difficult. Although bioinformatic algorithms predict that some variants may damage the encoded protein, these annotations are imperfect, and many rare variants remain unclassified and are clinically designated as variants of unknown significance (VUS) (2).Splicing signals reside at all exon-intron junctions and include a 9-bp 5′ splice donor sequence with an invariant GT dinucleotide and a 23-bp 3′ splice acceptor sequence with an invariant AG dinucleotide (3) (Fig. 1A). Variants that alter the canonical GT and AG dinucleotides in haploinsufficient autosomal dominant (AD) genes are diagnostically classified as pathogenic, whereas substitutions of the remaining seven residues within the donor sequence, or the 21 residues within the acceptor sequence, are often classified as VUS (4). VUS that alter these sequences, however, have the potential to disrupt normal RNA splicing (5) (resulting in donor or acceptor loss; Fig. 1C). Similarly, variants within a nearby intron or exon may sufficiently mimic the consensus donor...

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Section: Significancesupporting

confidence: 62%

Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing

Ito

Patel

Gorham

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…However, these variants seem to retain a generic capacity to trigger cardiac disease in the presence of environmental stimuli, creating a sort of nonspecific frailty of the myocardium. In a landmark study, a common 25 mb MYBPC3 deletion was associated with increased risk of heart failure in South Asians exposed to secondary risk factors, such as hypertension and hypercholesterolemia, posing a lifelong threat to carriers 76. Furthermore, a role for truncating titin mutations has been recently proposed in the development of peripartum cardiomyopathy,77 suggesting the possible interaction between a genetic predisposition and additional environmental (pregnancy) or genetic stimuli.…”

Section: Sarcomere Protein Gene Profile and Predisposition To Cardiacmentioning

confidence: 99%

Impact of Demographic Features, Lifestyle, and Comorbidities on the Clinical Expression of Hypertrophic Cardiomyopathy

Finocchiaro

Magavern

Sinagra

et al. 2017

JAHA

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“…The population incidence of sarcomere protein gene mutations is considerable (4)(5)(6), and recent epidemiologic studies document 7-fold increased risk of heart failure in the 40 million individuals estimated to carry these defects (4). Definition and inhibition of the signals that cause pathologic cardiac remodeling in response to sarcomere protein gene mutations may therefore have broad impact on human health.…”

mentioning

confidence: 99%

“…Introduction Dominant mutations in sarcomere protein genes cause hypertrophic cardiomyopathy (HCM), a primary myocardial disorder characterized by myocyte enlargement, increased myocardial fibrosis, and impaired ventricular relaxation that predisposes patients to develop heart failure (1)(2)(3)(4)(5). The population incidence of sarcomere protein gene mutations is considerable (4)(5)(6), and recent epidemiologic studies document 7-fold increased risk of heart failure in the 40 million individuals estimated to carry these defects (4).…”

mentioning

confidence: 99%

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

Teekakirikul¹,

Eminaga²,

Toka³

et al. 2010

J. Clin. Invest.

385

342

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Mutations in sarcomere protein genes can cause hypertrophic cardiomyopathy (HCM), a disorder characterized by myocyte enlargement, fibrosis, and impaired ventricular relaxation. Here, we demonstrate that sarcomere protein gene mutations activate proliferative and profibrotic signals in non-myocyte cells to produce pathologic remodeling in HCM. Gene expression analyses of non-myocyte cells isolated from HCM mouse hearts showed increased levels of RNAs encoding cell-cycle proteins, Tgf-β, periostin, and other profibrotic proteins. Markedly increased BrdU labeling, Ki67 antigen expression, and periostin immunohistochemistry in the fibrotic regions of HCM hearts confirmed the transcriptional profiling data. Genetic ablation of periostin in HCM mice reduced but did not extinguish non-myocyte proliferation and fibrosis. In contrast, administration of Tgf-β-neutralizing antibodies abrogated non-myocyte proliferation and fibrosis. Chronic administration of the angiotensin II type 1 receptor antagonist losartan to mutation-positive, hypertrophynegative (prehypertrophic) mice prevented the emergence of hypertrophy, non-myocyte proliferation, and fibrosis. Losartan treatment did not reverse pathologic remodeling of established HCM but did reduce nonmyocyte proliferation. These data define non-myocyte activation of Tgf-β signaling as a pivotal mechanism for increased fibrosis in HCM and a potentially important factor contributing to diastolic dysfunction and heart failure. Preemptive pharmacologic inhibition of Tgf-β signals warrants study in human patients with sarcomere gene mutations.

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A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia

Cited by 252 publications

References 27 publications

Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing

Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing

Impact of Demographic Features, Lifestyle, and Comorbidities on the Clinical Expression of Hypertrophic Cardiomyopathy

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

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