Two cases of severe neonatal hypertrophic cardiomyopathy caused by compound heterozygous mutations in the MYBPC3 gene

Deprez, Ronald H. Lekanne; Muurling-Vlietman, J J; Hruda, J; Baars, Marieke J.H.; Wijnaendts, Liliane C. D.; Stolte‐Dijkstra, Irene; Alders, Mariëlle; Hagen, Johanna M. van

doi:10.1136/jmg.2005.040329

Cited by 92 publications

(44 citation statements)

References 20 publications

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“…Here we show that Myk461 has salutary effects in reducing hypercontractility in myocardium lacking cMyBPC by decreasing the magnitude of force generation and the tension cost of force generation, which at the whole organ level would be expected to reduce systolic pressure generation, improve contractile efficiency, and reduce myocardial oxygen demands. Thus, development of Myk461‐based therapies may have utility in treating HCM patients expressing cMyBPC mutations, which are known to reduce the total amount of cMyBPC7 and induce severe cardiac dysfunction and death, especially at a young age 59, 60, 61. Our results define the mechanistic impact of Myk461 in hypercontractile myocardium lacking cMyBPC, and importantly, demonstrate that in KO myocardium Myk461‐induced force reductions were less pronounced than in WT myocardium.…”

Section: Discussionmentioning

confidence: 58%

“…Although far less common, there is clinical evidence showing that homozygous truncating mutations in cMyBPC exist and result in severe infantile HCM with poor prognosis and early death,59, 60, 61 likely because cMyBPC expression is either absent, or significantly lower than heterozygous mutation carriers. Our results therefore may be relevant in elucidating the clinical impact of Myk461 in conditions of severe cMyBPC deficiency, and provide insights of the role of cMyBPC in modulating the effects of Myk461 at the sarcomere level.…”

Section: Discussionmentioning

confidence: 99%

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Impact of the Myosin Modulator Mavacamten on Force Generation and Cross‐Bridge Behavior in a Murine Model of Hypercontractility

Mamidi

Doh

et al. 2018

JAHA

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BackgroundRecent studies suggest that mavacamten (Myk461), a small myosin‐binding molecule, decreases hypercontractility in myocardium expressing hypertrophic cardiomyopathy‐causing missense mutations in myosin heavy chain. However, the predominant feature of most mutations in cardiac myosin binding protein‐C (cMyBPC) that cause hypertrophic cardiomyopathy is reduced total cMyBPC expression, and the impact of Myk461 on cMyBPC‐deficient myocardium is currently unknown.Methods and ResultsWe measured the impact of Myk461 on steady‐state and dynamic cross‐bridge (XB) behavior in detergent‐skinned mouse wild‐type myocardium and myocardium lacking cMyBPC (knockout (KO)). KO myocardium exhibited hypercontractile XB behavior as indicated by significant accelerations in rates of XB detachment (krel) and recruitment (kdf) at submaximal Ca2+ activations. Incubation of KO and wild‐type myocardium with Myk461 resulted in a dose‐dependent force depression, and this impact was more pronounced at low Ca2+ activations. Interestingly, Myk461‐induced force depressions were less pronounced in KO myocardium, especially at low Ca2+ activations, which may be because of increased acto‐myosin XB formation and potential disruption of super‐relaxed XBs in KO myocardium. Additionally, Myk461 slowed krel in KO myocardium but not in wild‐type myocardium, indicating increased XB “on” time. Furthermore, the greater degree of Myk461‐induced slowing in kdf and reduction in XB recruitment magnitude in KO myocardium normalized the XB behavior back to wild‐type levels.ConclusionsThis is the first study to demonstrate that Myk461‐induced force depressions are modulated by cMyBPC expression levels in the sarcomere, and emphasizes that clinical use of Myk461 may need to be optimized based on the molecular trigger that underlies the hypertrophic cardiomyopathy phenotype.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Impact of the Myosin Modulator Mavacamten on Force Generation and Cross‐Bridge Behavior in a Murine Model of Hypercontractility

Mamidi

Doh

et al. 2018

JAHA

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“…First, it showed prevention of a disease phenotype, but no rescue. Yet, we believe that prevention is the more realistic scenario in the patient group we would like to target with the gene therapy approach, namely infants with severe homozygous or compound heterozygous mutations who quickly develop a therapy-resistant form of systolic heart failure 14,[16][17][18][19][20] . Second, mouse models including our KI model clearly differ from human HCM in that they show a much milder phenotype, generally only at the homozygous state 8,40,41 .…”

Section: Discussionmentioning

confidence: 99%

“…Whereas the mean life expectancy of patients who survived into young adulthood does not markedly differ from that of the normal population 12 , sudden cardiac death is common in young adults with HCM, particularly athletes 13 , and some patients develop severe systolic dysfunction and heart failure. Less known is that neonatal forms of HCM rapidly evolve into systolic heart failure and death within the first year of life [14][15][16][17][18][19][20] . Some of these infants have homozygous or compound heterozygous frameshift MYBPC3 mutations 14,[16][17][18][19][20] , expected to result in low level or absence of mutant cMyBP-C.…”

mentioning

confidence: 99%

“…Less known is that neonatal forms of HCM rapidly evolve into systolic heart failure and death within the first year of life [14][15][16][17][18][19][20] . Some of these infants have homozygous or compound heterozygous frameshift MYBPC3 mutations 14,[16][17][18][19][20] , expected to result in low level or absence of mutant cMyBP-C. Here we tested the easily generalizable idea to prevent the disease phenotype by adding full-length Mybpc3 by gene therapy in a Mybpc3-targeted knock-in (KI) mouse model 21,22 that genetically mimics the severe neonatal HCM cases 21,22 .…”

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confidence: 99%

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Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

et al. 2014

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Homozygous or compound heterozygous frameshift mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C) cause neonatal hypertrophic cardiomyopathy (HCM), which rapidly evolves into systolic heart failure and death within the first year of life. Here we show successful long-term Mybpc3 gene therapy in homozygous Mybpc3-targeted knock-in (KI) mice, which genetically mimic these human neonatal cardiomyopathies. A single systemic administration of adeno-associated virus (AAV9)-Mybpc3 in 1-day-old KI mice prevents the development of cardiac hypertrophy and dysfunction for the observation period of 34 weeks and increases Mybpc3 messenger RNA (mRNA) and cMyBP-C protein levels in a dose-dependent manner. Importantly, Mybpc3 gene therapy unexpectedly also suppresses accumulation of mutant mRNAs. This study reports the first successful long-term gene therapy of HCM with correction of both haploinsufficiency and production of poison peptides. In the absence of alternative treatment options except heart transplantation, gene therapy could become a realistic treatment option for severe neonatal HCM.

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Homozygosity for a novel splice site mutation in the cardiac myosin‐binding protein C gene causes severe neonatal hypertrophic cardiomyopathy

Xin

Puffenberger

Tumbush

et al. 2007

American J of Med Genetics Pt A

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Hypertrophic cardiomyopathy is typically inherited in an autosomal dominant pattern and has a variable age of onset and prognosis. Mutations in the myosin-binding protein C (MYBPC3) gene are one of the most frequent genetic causes of the disease. Patients with MYBPC3 mutations generally have a late onset and a relatively good prognosis. We report here more than 20 Old Order Amish children with severe neonatal hypertrophic cardiomyopathy caused by a novel homozygous splice site mutation in the MYBPC3 gene. The affected children typically presented with signs and symptoms of congestive heart failure during the first 3 weeks of life. Echocardiography revealed hypertrophic non-obstructive cardiomyopathy. These children had a life span averaging 3-4 months. All patients died from heart failure before 1 year of age unless they received a heart transplant. A genome-wide mapping study was performed in three patients. The disease related gene was localized to a 4.6 Mb region on chromosome 11p11.2-p11.12. This homozygous block contained MYBPC3, a previously identified cardiomyopathy related gene. We identified a novel homozygous mutation, c.3330 + 2T> G, in the splice-donor site of MYBPC3 intron 30. The mutation resulted in skipping of the 140-bp exon 30, which led to a frame shift and premature stop codon in exon 31 (p.Asp1064GlyfsX38). We have found a substantial incidence of this phenotype in Old Order Amish communities. It is also concerning that many unidentified heterozygous individuals who are at risk for development of hypertrophic cardiomyopathy do not receive proper medical attention in the communities.

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Two cases of severe neonatal hypertrophic cardiomyopathy caused by compound heterozygous mutations in the MYBPC3 gene

Cited by 92 publications

References 20 publications

Impact of the Myosin Modulator Mavacamten on Force Generation and Cross‐Bridge Behavior in a Murine Model of Hypercontractility

Impact of the Myosin Modulator Mavacamten on Force Generation and Cross‐Bridge Behavior in a Murine Model of Hypercontractility

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

Homozygosity for a novel splice site mutation in the cardiac myosin‐binding protein C gene causes severe neonatal hypertrophic cardiomyopathy

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