Related Experiment Video

Updated: Jul 11, 2025

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model

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Compound Heterozygosity for Late-Onset Cardiomyopathy-Causative ALPK3 Coding Variant and Novel Intronic Variant Cause

Tomer Poleg1, Marina Eskin-Schwartz1,2, Regina Proskorovski-Ohayon1

  • 1The Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.

Journal of Cardiovascular Translational Research
|November 16, 2023
PubMed

Insights

Genetic variants in alpha-protein kinase 3 (ALPK3) cause infantile and adult-onset hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), expanding the understanding of these heart conditions.

Area of Science:

  • Genetics
  • Cardiology
  • Molecular Biology

Background:

  • Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are significant causes of pediatric cardiovascular disease.
  • The pseudokinase alpha-protein kinase 3 (ALPK3) is crucial for sarcomere organization and cardiomyocyte development.
  • ALPK3 mutations are linked to both inherited pediatric and adult-onset cardiomyopathies.

Purpose of the Study:

  • To investigate novel variants in the ALPK3 gene.
  • To elucidate the genotypic spectrum and phenotypic variability of ALPK3-related cardiomyopathies.
  • To validate the role of ALPK3 in both recessive and dominant forms of heart disease.

Main Methods:

  • Genetic sequencing to identify ALPK3 variants.
  • Analysis of patient phenotypes, including cardiac abnormalities, facial dysmorphism, and skeletal features.
  • Correlation of genotype with clinical presentation and inheritance patterns.

Main Results:

  • Two novel ALPK3 variants were identified: a coding variant and an intronic splicing variant.
  • Compound heterozygosity for both variants was associated with infantile-onset HCM and Noonan-like features.
  • Heterozygosity for the coding variant presented as adult-onset HCM, demonstrating partial penetrance.

Conclusions:

  • The study expands the known genetic causes of ALPK3-related cardiomyopathies.
  • Partial penetrance of heterozygous ALPK3 loss-of-function mutations contributes to late-onset hypertrophic cardiomyopathy.
  • ALPK3 variants are implicated in a spectrum of inherited cardiac conditions with variable clinical presentations.

Keywords:
ALPK3CardiomyopathyDCMHCMSplice site mutation

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