Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated Cardiomyopathy

David Y. Barefield, Megan J Roy-Puckelwartz, Ellis Y. Kim, Lisa D Wilsbacher, Andy H. Vo, Emily A. Waters, Judy U. Earley, Michele Hadhazy, Lisa Marie Castillo, Lorenzo Luigi Pesce, Elizabeth M McNally*

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Cardiomyopathy and arrhythmias are under significant genetic influence. Here, we studied a family with dilated cardiomyopathy and associated conduction system disease in whom prior clinical cardiac gene panel testing was unrevealing. Methods: Whole-genome sequencing and induced pluripotent stem cells were used to examine a family with dilated cardiomyopathy and atrial and ventricular arrhythmias. We also characterized a mouse model with heterozygous and homozygous deletion of Mybphl. Results: Whole-genome sequencing identified a premature stop codon, R255X, in the MYBPHL gene encoding MyBP-HL (myosin-binding protein-H like), a novel member of the myosin-binding protein family. MYBPHL was found to have high atrial expression with low ventricular expression. We determined that MyBP-HL protein was myofilament associated in the atria, and truncated MyBP-HL protein failed to incorporate into the myofilament. Human cell modeling demonstrated reduced expression from the mutant MYBPHL allele. Echocardiography of Mybphl heterozygous and null mouse hearts exhibited a 36% reduction in fractional shortening and an increased diastolic ventricular chamber size. Atria weight normalized to total heart weight was significantly increased in Mybphl heterozygous and null mice. Using a reporter system, we detected robust expression of Mybphl in the atria, and in discrete puncta throughout the right ventricular wall and septum, as well. Telemetric electrocardiogram recordings in Mybphl mice revealed cardiac conduction system abnormalities with aberrant atrioventricular conduction and an increased rate of arrhythmia in heterozygous and null mice. Conclusions: The findings of reduced ventricular function and conduction system defects in Mybphl mice support that MYBPHL truncations may increase risk for human arrhythmias and cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)1477-1491
Number of pages15
JournalCirculation
Volume136
Issue number16
DOIs
StatePublished - Oct 17 2017

Fingerprint

Myofibrils
Dilated Cardiomyopathy
Myosins
Cardiac Arrhythmias
Carrier Proteins
Cardiomyopathies
Genome
Weights and Measures
Induced Pluripotent Stem Cells
Ventricular Septum
Ventricular Function
Nonsense Codon
Genes
Echocardiography
Electrocardiography
Proteins
Alleles

Keywords

  • arrhythmias, cardiac
  • cardiomyopathies
  • genetics
  • heart atria
  • mice
  • mutation
  • myofibrils

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

@article{b8755ce2c6624e289217a0b19a9da2bb,
title = "Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated Cardiomyopathy",
abstract = "Background: Cardiomyopathy and arrhythmias are under significant genetic influence. Here, we studied a family with dilated cardiomyopathy and associated conduction system disease in whom prior clinical cardiac gene panel testing was unrevealing. Methods: Whole-genome sequencing and induced pluripotent stem cells were used to examine a family with dilated cardiomyopathy and atrial and ventricular arrhythmias. We also characterized a mouse model with heterozygous and homozygous deletion of Mybphl. Results: Whole-genome sequencing identified a premature stop codon, R255X, in the MYBPHL gene encoding MyBP-HL (myosin-binding protein-H like), a novel member of the myosin-binding protein family. MYBPHL was found to have high atrial expression with low ventricular expression. We determined that MyBP-HL protein was myofilament associated in the atria, and truncated MyBP-HL protein failed to incorporate into the myofilament. Human cell modeling demonstrated reduced expression from the mutant MYBPHL allele. Echocardiography of Mybphl heterozygous and null mouse hearts exhibited a 36{\%} reduction in fractional shortening and an increased diastolic ventricular chamber size. Atria weight normalized to total heart weight was significantly increased in Mybphl heterozygous and null mice. Using a reporter system, we detected robust expression of Mybphl in the atria, and in discrete puncta throughout the right ventricular wall and septum, as well. Telemetric electrocardiogram recordings in Mybphl mice revealed cardiac conduction system abnormalities with aberrant atrioventricular conduction and an increased rate of arrhythmia in heterozygous and null mice. Conclusions: The findings of reduced ventricular function and conduction system defects in Mybphl mice support that MYBPHL truncations may increase risk for human arrhythmias and cardiomyopathy.",
keywords = "arrhythmias, cardiac, cardiomyopathies, genetics, heart atria, mice, mutation, myofibrils",
author = "Barefield, {David Y.} and Roy-Puckelwartz, {Megan J} and Kim, {Ellis Y.} and Wilsbacher, {Lisa D} and Vo, {Andy H.} and Waters, {Emily A.} and Earley, {Judy U.} and Michele Hadhazy and Castillo, {Lisa Marie} and Pesce, {Lorenzo Luigi} and McNally, {Elizabeth M}",
year = "2017",
month = "10",
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doi = "10.1161/CIRCULATIONAHA.117.028585",
language = "English (US)",
volume = "136",
pages = "1477--1491",
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issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
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Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated Cardiomyopathy. / Barefield, David Y.; Roy-Puckelwartz, Megan J; Kim, Ellis Y.; Wilsbacher, Lisa D; Vo, Andy H.; Waters, Emily A.; Earley, Judy U.; Hadhazy, Michele; Castillo, Lisa Marie; Pesce, Lorenzo Luigi; McNally, Elizabeth M.

In: Circulation, Vol. 136, No. 16, 17.10.2017, p. 1477-1491.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated Cardiomyopathy

AU - Barefield, David Y.

AU - Roy-Puckelwartz, Megan J

AU - Kim, Ellis Y.

AU - Wilsbacher, Lisa D

AU - Vo, Andy H.

AU - Waters, Emily A.

AU - Earley, Judy U.

AU - Hadhazy, Michele

AU - Castillo, Lisa Marie

AU - Pesce, Lorenzo Luigi

AU - McNally, Elizabeth M

PY - 2017/10/17

Y1 - 2017/10/17

N2 - Background: Cardiomyopathy and arrhythmias are under significant genetic influence. Here, we studied a family with dilated cardiomyopathy and associated conduction system disease in whom prior clinical cardiac gene panel testing was unrevealing. Methods: Whole-genome sequencing and induced pluripotent stem cells were used to examine a family with dilated cardiomyopathy and atrial and ventricular arrhythmias. We also characterized a mouse model with heterozygous and homozygous deletion of Mybphl. Results: Whole-genome sequencing identified a premature stop codon, R255X, in the MYBPHL gene encoding MyBP-HL (myosin-binding protein-H like), a novel member of the myosin-binding protein family. MYBPHL was found to have high atrial expression with low ventricular expression. We determined that MyBP-HL protein was myofilament associated in the atria, and truncated MyBP-HL protein failed to incorporate into the myofilament. Human cell modeling demonstrated reduced expression from the mutant MYBPHL allele. Echocardiography of Mybphl heterozygous and null mouse hearts exhibited a 36% reduction in fractional shortening and an increased diastolic ventricular chamber size. Atria weight normalized to total heart weight was significantly increased in Mybphl heterozygous and null mice. Using a reporter system, we detected robust expression of Mybphl in the atria, and in discrete puncta throughout the right ventricular wall and septum, as well. Telemetric electrocardiogram recordings in Mybphl mice revealed cardiac conduction system abnormalities with aberrant atrioventricular conduction and an increased rate of arrhythmia in heterozygous and null mice. Conclusions: The findings of reduced ventricular function and conduction system defects in Mybphl mice support that MYBPHL truncations may increase risk for human arrhythmias and cardiomyopathy.

AB - Background: Cardiomyopathy and arrhythmias are under significant genetic influence. Here, we studied a family with dilated cardiomyopathy and associated conduction system disease in whom prior clinical cardiac gene panel testing was unrevealing. Methods: Whole-genome sequencing and induced pluripotent stem cells were used to examine a family with dilated cardiomyopathy and atrial and ventricular arrhythmias. We also characterized a mouse model with heterozygous and homozygous deletion of Mybphl. Results: Whole-genome sequencing identified a premature stop codon, R255X, in the MYBPHL gene encoding MyBP-HL (myosin-binding protein-H like), a novel member of the myosin-binding protein family. MYBPHL was found to have high atrial expression with low ventricular expression. We determined that MyBP-HL protein was myofilament associated in the atria, and truncated MyBP-HL protein failed to incorporate into the myofilament. Human cell modeling demonstrated reduced expression from the mutant MYBPHL allele. Echocardiography of Mybphl heterozygous and null mouse hearts exhibited a 36% reduction in fractional shortening and an increased diastolic ventricular chamber size. Atria weight normalized to total heart weight was significantly increased in Mybphl heterozygous and null mice. Using a reporter system, we detected robust expression of Mybphl in the atria, and in discrete puncta throughout the right ventricular wall and septum, as well. Telemetric electrocardiogram recordings in Mybphl mice revealed cardiac conduction system abnormalities with aberrant atrioventricular conduction and an increased rate of arrhythmia in heterozygous and null mice. Conclusions: The findings of reduced ventricular function and conduction system defects in Mybphl mice support that MYBPHL truncations may increase risk for human arrhythmias and cardiomyopathy.

KW - arrhythmias, cardiac

KW - cardiomyopathies

KW - genetics

KW - heart atria

KW - mice

KW - mutation

KW - myofibrils

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U2 - 10.1161/CIRCULATIONAHA.117.028585

DO - 10.1161/CIRCULATIONAHA.117.028585

M3 - Article

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SP - 1477

EP - 1491

JO - Circulation

JF - Circulation

SN - 0009-7322

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ER -