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KCNA2 variants cause dilated cardiomyopathy, obesity and sleep apnea through RAC-ERK pathway

Prasanth Chimata1,2, Sahil Lall3, Tarmo Annilo4

  • 1Cardiovascular Development and Disease Mechanisms, Institute for Stem Cell Science and Regenerative Medicine (BRIC-inStem), Bengaluru, Karnataka, 560065, India.

EMBO Molecular Medicine
|February 24, 2026
PubMed

Insights

Genetic KCNA2 variants are linked to a heart condition (DCM), obesity, and sleep apnea (DOSA). These variants cause ion channel dysfunction, impacting heart function and leading to DOSA phenotypes.

Area of Science:

  • Cardiovascular Genetics
  • Channelopathies
  • Systems Biology

Background:

  • Dilated cardiomyopathy (DCM) involves heart dysfunction, often co-occurring with obesity and sleep apnea.
  • The genetic basis for these combined phenotypes (DCM, obesity, sleep apnea - DOSA) remains largely unknown.

Purpose of the Study:

  • To investigate the genetic underpinnings of patients presenting with DCM, obesity, and sleep apnea (DOSA).
  • To elucidate the functional consequences of identified genetic variants in disease pathogenesis.

Main Methods:

  • Next-generation sequencing to identify genetic variants in DOSA patients.
  • Electrophysiological and biochemical assays using biosensors to assess variant function.
  • Patient-derived iPSC cardiomyocytes and organoid models for cellular studies.
  • Drosophila melanogaster model to validate in vivo phenotypes and therapeutic targets.

Main Results:

  • Pathogenic KCNA2 variants were identified in diverse ancestry DOSA patients.
  • KCNA2 variants led to loss of membrane current due to cellular trafficking defects.
  • Hyperactivation of the RAC1-ERK1/2 pathway was observed in cellular models.
  • A Drosophila model exhibited DOSA-like phenotypes, reversible with RAC1 inhibitors.

Conclusions:

  • This study provides the first evidence linking KCNA2 variants to the combined phenotypes of DCM, obesity, and sleep apnea (DOSA).
  • KCNA2 variants disrupt potassium channel function, contributing to DOSA pathogenesis via RAC1-ERK1/2 pathway dysregulation.
  • These findings expand the known roles of potassium channels in complex human diseases.

Keywords:
Dilated CardiomyopathyObesitySleep Apnea

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