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Published on: March 12, 2013

A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden

Ping Ouyang1, Elizabeth Saarel, Ying Bai

  • 1Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, and Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, PR China.

Clinica Chimica Acta; International Journal of Clinical Chemistry
|October 12, 2010
PubMed

Insights

A novel NKX2.5 gene mutation (c.512insGC) causes congenital heart defects, including atrial septal defects and ventricular noncompaction, leading to severe symptoms like syncope and sudden death in a family.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cardiology

Background:

  • Transcription factor NKX2.5 mutations are a known cause of congenital heart disease (CHD).
  • A family presented with a severe CHD phenotype including atrial septal defects (ASDs), atrioventricular block, ventricular noncompaction, syncope, and sudden death.

Purpose of the Study:

  • To identify the specific genetic mutation responsible for CHD in the affected family.
  • To elucidate the functional consequences of the identified mutation on NKX2.5 protein activity.

Main Methods:

  • Direct DNA sequencing was employed to detect mutations in the NKX2.5 gene.
  • Functional characterization involved luciferase reporter assays and immunostaining to assess protein localization and activity.

Main Results:

  • A novel, de novo 2-bp insertion (c.512insGC) in exon 2 of NKX2.5 was identified and co-segregated with CHD in the family.
  • The c.512insGC mutation impaired NKX2.5 nuclear localization and abolished its transactivation activity.
  • No NKX2.5 mutations were found in 125 sporadic Chinese CHD patients, suggesting rarity in sporadic cases.

Conclusions:

  • The NKX2.5 mutation c.512insGC is linked to ASDs, syncope, and sudden death, expanding the known spectrum of NKX2.5-related disorders.
  • This represents the second identified de novo NKX2.5 mutation.
  • The study provides the first evidence associating an NKX2.5 mutation with ventricular noncompaction.
Abstract

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