A Homozygous MYBPC3 Gene Mutation Associated With a Severe Phenotype and a High Risk of Sudden Death in a Family With Hypertrophic Cardiomyopathy

Ortiz, Martín; Rodríguez-García, Marìa Isabel; Hermida-Prieto, Manuel; Fernández, Xusto; Veira, Elena; Barriales‐Villa, Roberto; Castro‐Beiras, Alfonso; Monserrat, Lorenzo

doi:10.1016/s1885-5857(09)71841-9

Cited by 8 publications

(6 citation statements)

References 14 publications

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“…All mutations appeared in heterozygousis, except for IVS6+5G>A, which showed up in homozygousis as we have previously reported [19]. None of the patients with mutations in MyBPC3 showed mutations in MYH7 .…”

Section: Resultssupporting

confidence: 76%

“…In fact, the youngest SD (15 and 26 year old) are in the IVS6+5G>A index cases families, and these individuals are likely to be in homozygousis as in the index case. This fact could support a gene dossage effect for mutations in the MyBPC3 gene that have been previously described where a homozygous mutation is associated with a more severe phenotype than the heterozygous [19]. …”

Section: Discussionsupporting

confidence: 72%

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Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy

et al. 2010

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BackgroundMyBPC3 mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, however, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Our objectives were to establish the prevalence of MyBPC3 mutations and determine their associated clinical characteristics in our patients.MethodsScreening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the MyBPC3 gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families.Results16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with MYH7 mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9].ConclusionsMutations in MyBPC3 are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of MyBPC3 mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM.

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Section: Resultssupporting

confidence: 76%

Section: Discussionsupporting

confidence: 72%

Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy

et al. 2010

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“…The development of cMyBPC gene therapy may be especially useful in the treatment of patients with compound heterozygous or homozygous cMyBPC mutations, which may result in significant reductions in the content of cMyBPC in the sarcomere, and are associated with severe cardiac dysfunction and high incidences of death at a young age. 32–34 …”

Section: Discussionmentioning

confidence: 99%

In Vivo Cardiac Myosin Binding Protein C Gene Transfer Rescues Myofilament Contractile Dysfunction in Cardiac Myosin Binding Protein C Null Mice

Merkulov

Chen

Chandler

et al. 2012

Circ: Heart Failure

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Background Decreased expression of cardiac myosin binding protein C (cMyBPC) in the heart has been implicated as a consequence of mutations in cMyBPC that lead to abnormal contractile function at the myofilament level, thereby contributing to the development of hypertrophic cardiomyopathy in humans. It has not been established whether increasing the levels of cMyBPC in the intact heart can improve myofilament and in vivo contractile function and attenuate maladaptive remodeling processes because of reduced levels of cMyBPC. Methods and Results We performed in vivo gene transfer of cMyBPC by direct injection into the myocardium of cMyBPC-deficient (cMyBPC−/−) mice, and mechanical experiments were conducted on skinned myocardium isolated from cMyBPC−/− hearts 21 days and 20 weeks after gene transfer. Cross-bridge kinetics in skinned myocardium isolated from cMyBPC−/− hearts after cMyBPC gene transfer were significantly slower compared with untreated cMyBPC−/− myocardium and were comparable to wild-type myocardium and cMyBPC−/− myocardium that was reconstituted with recombinant cMyBPC in vitro. cMyBPC content in cMyBPC−/− skinned myocardium after in vivo cMyBPC gene transfer or in vitro cMyBPC reconstitution was similar to wild-type levels. In vivo echocardiography studies of cMyBPC−/− hearts after cMyBPC gene transfer revealed improved systolic and diastolic contractile function and reductions in left ventricular wall thickness. Conclusions This proof-of-concept study demonstrates that gene therapy designed to increase expression of cMyBPC in the cMyBPC-deficient myocardium can improve myofilament and in vivo contractile function, suggesting that cMyBPC gene therapy may be a viable approach for treatment of cardiomyopathies because of mutations in cMyBPC.

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“…This suggests that a gene-dosage effect might be responsible for manifestations at a younger age. A total of 51 cases of homozygotes or compound heterozygotes have been reported, composed of 26 cases with double truncating mutations (Richard et al, 2003; Lekanne Deprez et al, 2006; Xin et al, 2007; Zahka et al, 2008; Ortiz et al, 2009; Tajsharghi et al, 2010; Marziliano et al, 2012; Schaefer et al, 2014; Wessels et al, 2014), 11 cases with a missense plus a truncating mutations (Richard et al, 2003; Ingles et al, 2005; Morita et al, 2008; Dellefave et al, 2009; Saltzman et al, 2010; Otsuka et al, 2012), and 14 with bi-allelic missense mutations (Nanni et al, 2003; Van Driest et al, 2004; Garcia-Castro et al, 2005; Ingles et al, 2005; Morita et al, 2008; Saltzman et al, 2010; Maron et al, 2012). These studies also showed that all patients with bi-allelic truncating MYBPC3 mutations are associated with neonatal cardiomyopathy and lead to heart failure and death within the first year of life.…”

Section: Mybpc3 and Inherited Cardiomyopathiesmentioning

confidence: 99%

Cardiac myosin-binding protein C (MYBPC3) in cardiac pathophysiology

Carrier

Mearini

Σταθοπούλου

et al. 2015

Gene

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More than 350 individual MYPBC3 mutations have been identified in patients with inherited hypertrophic cardiomyopathy (HCM), thus representing 40–50% of all HCM mutations, making it the most frequently mutated gene in HCM. HCM is considered a disease of the sarcomere and is characterized by left ventricular hypertrophy, myocyte disarray and diastolic dysfunction. MYBPC3 encodes for the thick filament associated protein cardiac myosin-binding protein C (cMyBP-C), a signaling node in cardiac myocytes that contributes to the maintenance of sarcomeric structure and regulation of contraction and relaxation. This review aims to provide a succinct overview of how mutations in MYBPC3 are considered to affect the physiological function of cMyBP-C, thus causing the deleterious consequences observed inHCM patients. Importantly, recent advances to causally treat HCM by repairing MYBPC3 mutations by gene therapy are discussed here, providing a promising alternative to heart transplantation for patients with a fatal form of neonatal cardiomyopathy due to bi-allelic truncating MYBPC3 mutations.

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A Homozygous MYBPC3 Gene Mutation Associated With a Severe Phenotype and a High Risk of Sudden Death in a Family With Hypertrophic Cardiomyopathy

Cited by 8 publications

References 14 publications

Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy

Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy

In Vivo Cardiac Myosin Binding Protein C Gene Transfer Rescues Myofilament Contractile Dysfunction in Cardiac Myosin Binding Protein C Null Mice

Cardiac myosin-binding protein C (MYBPC3) in cardiac pathophysiology

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