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Whole-exome sequencing identifies a novel mutation of GPD1L (R189X) associated with familial conduction disease and

Hao Huang1, Ya-Qin Chen2, Liang-Liang Fan1

  • 1School of Life Sciences, Central South University, Changsha, China.

Journal of Cellular and Molecular Medicine
|October 28, 2017
PubMed

Insights

A novel glycerol-3-phosphate dehydrogenase-like (GPD1L) mutation causes cardiac conduction disease (CCD) by disrupting Nav1.5 function. This finding expands GPD1L mutation spectrum and aids genetic diagnosis for families with arrhythmia and syncope.

Area of Science:

  • Genetics
  • Cardiology
  • Molecular Biology

Background:

  • Cardiac conduction disease (CCD) is a major global health concern, leading to arrhythmia, syncope, and sudden cardiac death.
  • Dysfunction of cardiac voltage-gated channels is a primary cause of CCD, with mutations in related genes being key genetic culprits.
  • Glycerol-3-phosphate dehydrogenase-like (GPD1L) interacts with SCN5A, a gene critical for cardiac sodium channel Nav1.5 function, implicated in Brugada syndrome.

Purpose of the Study:

  • To identify causative genes in a Chinese family exhibiting ventricular tachycardia and syncope using whole-exome sequencing.
  • To investigate the role of a novel GPD1L mutation in the pathogenesis of cardiac conduction disease.

Main Methods:

  • Whole-exome sequencing was performed to identify genetic variations in affected family members.
  • A novel nonsense mutation (c.565C>T/p.R189X) in the GPD1L gene was identified and its co-segregation with the disease phenotype was confirmed.
  • Functional studies, including Western blot analysis in HEK293 cells, were conducted to assess the impact of the mutation on GPD1L expression and function.

Main Results:

  • A novel nonsense mutation, c.565C>T/p.R189X, in the GPD1L gene was identified and segregated with ventricular tachycardia and syncope in the studied family.
  • This mutation introduces a premature stop codon, leading to functional haploinsufficiency of GPD1L, likely due to nonsense-mediated mRNA decay.
  • Reduced GPD1L levels were confirmed, suggesting a disruption of Nav1.5 channel function and potential induction of arrhythmia and syncope.

Conclusions:

  • The study reinforces the critical role of GPD1L in cardiac conduction disease.
  • The identified novel mutation expands the known spectrum of GPD1L mutations associated with CCD.
  • These findings are valuable for genetic diagnosis and counseling of families affected by cardiac conduction disorders.

Keywords:
GPDL1cardiac conduction diseasesnonsenseventricular tachycardiawhole-exome sequencing

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