A Novel Founder Mutation in MYBPC3: Phenotypic Comparison With the Most Prevalent MYBPC3 Mutation in Spain

Sabater-Molina, María; Saura, Daniel; Sáez, Esperanza García-Molina; González-Carrillo, Josefa; Polo, Luis; Pérez-Sánchez, Inmaculada; Olmo, María del Carmen; Oliva-Sandoval, María José; Barriales‐Villa, Roberto; Carbonell, Pablo; Pascual-Figal, Domingo A.; Gimeno, Juan R.

doi:10.1016/j.rec.2016.06.020

“…Larger studies focused on a single variant, such as the c.1504C>T variant in the MYBPC3 gene, have elucidated more data on disease penetrance and severity. 18,24 This study highlights the importance of sharing genetic test results to facilitate variant classification and explore possible genotype-phenotype relationships. The majority of families with a causal variant identified carry a nonunique variant that has been identified in patients around the world.…”

Section: Genotype-phenotype Associationsmentioning

confidence: 99%

“…Delayed disease onset and incomplete penetrance may explain why founder variants that cause HCM, such as MYBPC3 c.2373dupG, escape negative selection pressures to cause disease across many generations. 12,16,18 There were 11 common recurrent variants, 7 of which are C to T transitions at a CpG dinucleotide. The cytosine of a CpG dinucleotide is often methylated and can spontaneously deaminate, producing a T:G mismatch, which can lead to a C to T transition mutation.…”

Section: Genotype-phenotype Associationsmentioning

confidence: 99%

Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy

Ross

¹

,

Bagnall

²

,

Ingles

³

et al. 2017

Circ Cardiovasc Genet

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“…Dominant pathogenic variants in eight sarcomere genes cause HCM, but predominate in MYBPC3 and MYH7 (encoding β cardiac myosin heavy chain; β-MHC) 4 . The overwhelming majority of HCM founder mutations [5][6][7][8][9][10][11] , including one affecting 4% of South Asians 12 reside in MYBPC3. All HCM mutations in MYH7 encode missense substitutions 4 and mutant myosins are incorporated into the sarcomere.…”

Section: Introductionmentioning

confidence: 99%

MYBPC3 Mutations cause Hypertrophic Cardiomyopathy by Dysregulating Myosin: Implications for Therapy

Toepfer

¹

,

Wakimoto

²

,

Garfinkel

³

et al. 2018

Preprint

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One Sentence Summary: Analyses of cardiomyocytes with hypertrophic cardiomyopathy mutations in MYBPC3 reveal that these directly activate myosin contraction by disrupting myosin states of relaxation, and that genetic or pharmacological manipulation of myosin therapeutically abates the effects of MYBPC3 mutations.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/304204 doi: bioRxiv preprint first posted online Apr. 18, 2018; 2 Abstract: The mechanisms by which truncating mutations in MYBPC3 (encoding cardiac myosin binding protein-C; cMyBPC) or myosin missense mutations cause hyper-contractility and poor relaxation in hypertrophic cardiomyopathy (HCM) are incompletely understood. Using genetic and biochemical approaches we explored how depletion of cMyBPC altered sarcomere function. We demonstrate that stepwise loss of cMyBPC resulted in reciprocal augmentation of myosin contractility. Direct attenuation of myosin function, via a damaging missense variant (F764L) that causes dilated cardiomyopathy (DCM) normalized the increased contractility from cMyBPC depletion. Depletion of cMyBPC also altered dynamic myosin conformations during relaxation -enhancing the myosin state that enables ATP hydrolysis and thin filament interactions while reducing the super relaxed conformation associated with energy conservation. MYK-461, a pharmacologic inhibitor of myosin ATPase, rescued relaxation deficits and restored normal contractility in mouse and human cardiomyocytes with MYBPC3 mutations. These data define dosage-dependent effects of cMyBPC on myosin that occur across all phases of the cardiac cycle as the pathophysiologic mechanisms by which MYBPC3 truncations cause HCM. Therapeutic strategies to attenuate cMyBPC activity may rescue depressed cardiac contractility in DCM patients, while inhibiting myosin by MYK-461 should benefit the substantial proportion of HCM patients with MYBPC3 mutations.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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“…Dominant pathogenic variants in eight sarcomere genes cause HCM, but predominate in MYBPC3 and MYH7 (encoding β cardiac myosin heavy chain; β-MHC) 4 . The overwhelming majority of HCM founder mutations [5][6][7][8][9][10][11] , including one affecting 4% of South Asians 12 reside in MYBPC3. All HCM mutations in MYH7 encode missense substitutions 4 and mutant myosins are incorporated into the sarcomere.…”

Section: Introductionmentioning

confidence: 99%

Abstract 571: MYBPC3 Mutations Cause Hypertrophic Cardiomyopathy by Dysregulating Myosin: Implications for Therapy

Toepfer¹,

Wakimoto²,

Garfinkel³

et al. 2018

Circulation Research

0

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A Novel Founder Mutation in MYBPC3: Phenotypic Comparison With the Most Prevalent MYBPC3 Mutation in Spain

Cited by 16 publications

References 42 publications

Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy

Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy

MYBPC3 Mutations cause Hypertrophic Cardiomyopathy by Dysregulating Myosin: Implications for Therapy

Abstract 571: MYBPC3 Mutations Cause Hypertrophic Cardiomyopathy by Dysregulating Myosin: Implications for Therapy

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