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Perturbation of NCOA6 leads to dilated cardiomyopathy

Jae-Il Roh1, Cheolho Cheong2, Young Hoon Sung1

  • 1Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; Yonsei Laboratory Animal Research Center, Yonsei University, Seoul 120-749, South Korea.

Cell Reports
|August 19, 2014
PubMed

Insights

Mutations in the NCOA6 gene are linked to dilated cardiomyopathy (DCM), a serious heart condition. This discovery offers new insights into the genetic causes of DCM in adults.

Area of Science:

  • Cardiovascular Biology
  • Molecular Genetics
  • Human Disease Genetics

Background:

  • Dilated cardiomyopathy (DCM) is a progressive heart condition marked by left ventricular enlargement and impaired contractility.
  • While mouse models have identified candidate genes, their direct link to human DCM remains limited.
  • Nuclear hormone receptor coactivator 6 (NCOA6) deficiency causes embryonic lethality and heart defects, but its role in adult heart disease is unknown.

Purpose of the Study:

  • To investigate the role of NCOA6 dysfunction in adult dilated cardiomyopathy.
  • To determine if mutations in NCOA6 are associated with idiopathic DCM (iDCM) in human patients.

Main Methods:

  • Generated and analyzed two independent mouse models with NCOA6 dysfunction.
  • Assessed cardiac function, mitochondrial function, and peroxisome proliferator-activated receptor delta (PPARδ) activity in mouse models.
  • Sequenced NCOA6-coding regions in patients diagnosed with idiopathic DCM.

Main Results:

  • Mouse models of NCOA6 dysfunction exhibited severe DCM, impaired mitochondrial function, and reduced PPARδ activity.
  • Three distinct nonsynonymous NCOA6 mutations were identified in 5 out of 50 (10%) iDCM patients.
  • NCOA6 is a critical target for PPARδ, which is essential for normal heart function.

Conclusions:

  • NCOA6 dysfunction can lead to severe dilated cardiomyopathy in mouse models.
  • NCOA6 mutations are present in a subset of patients with idiopathic DCM, suggesting a causal link.
  • NCOA6 plays a crucial role in maintaining adult heart function, potentially through its regulation of PPARδ.

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