Mutations in the tail domain of MYH3 contributes to atrial septal defect

PLoS One. 2020 Apr 21;15(4):e0230982. doi: 10.1371/journal.pone.0230982. eCollection 2020.

Abstract

Atrial septal defect (ASD) is one of the most common congenital heart defects diagnosed in children. Sarcomeric genes has been attributed to ASD and knockdown of MYH3 functionally homologues gene in chick models indicated abnormal atrial septal development. Here, we report for the first time, a case-control study investigating the role of MYH3 among non-syndromic ASD patients in contributing to septal development. Four amplicons which will amplifies the 40 kb MYH3 were designed and amplified using long range-PCR. The amplicons were then sequenced using indexed paired-end libraries on the MiSeq platform. The STREGA guidelines were applied for planning and reporting. The non-synonymous c. 3574G>A (p.Ala1192Thr) [p = 0.001, OR = 2.30 (1.36-3.87)] located within the tail domain indicated a highly conserved protein region. The mutant model of c. 3574G>A (p.Ala1192Thr) showed high root mean square deviation (RMSD) values compared to the wild model. To our knowledge, this is the first study to provide compelling evidence on the pathogenesis of MYH3 variants towards ASD hence, suggesting the crucial role of non-synonymous variants in the tail domain of MYH3 towards atrial septal development. It is hoped that this gene can be used as panel for diagnosis of ASD in future.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Base Sequence
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Conserved Sequence
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / genetics*
  • Female
  • Heart Septal Defects, Atrial / genetics*
  • Humans
  • Male
  • Middle Aged
  • Models, Genetic
  • Models, Molecular
  • Mutation*
  • Mutation, Missense
  • Myosin Heavy Chains / chemistry
  • Myosin Heavy Chains / genetics*
  • Myosin Type III / chemistry
  • Myosin Type III / genetics*
  • Polymorphism, Single Nucleotide
  • Young Adult

Substances

  • Cytoskeletal Proteins
  • MYH3 polypeptide, human
  • Myosin Type III
  • Myosin Heavy Chains

Associated data

  • Dryad/10.5061/dryad.pvmcvdnh3

Grants and funding

This work was funded by the Research University Grant (RU), Universiti Sains Malaysia [1001/PPSP/813066] and Fundamental Research Grant Scheme, Ministry of Education Malaysia [FRGS/1/2018/SKK11/PERDANA/02/1]. THL and SHEL were the respective Principle investigators. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.