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J Med Genet 41:684-690 doi:10.1136/jmg.2003.017483
  • Short report

Somatic NKX2-5 mutations as a novel mechanism of disease in complex congenital heart disease

  1. S M Reamon-Buettner,
  2. J Borlak
  1. Drug Research and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Strasse 1, D-30625 Hanover, Germany
  1. Correspondence to:
 J Borlak
 Drug Research and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Strasse 1, D-30625 Hanover, Germany; borlakitem.fraunhofer.de
  • Received 9 April 2004
  • Accepted 13 April 2004

Abstract

NKX2–5 is a pivotal transcription factor in heart development. Previous studies on lymphocytic DNA provided evidence of familial NKX2–5 gene mutations in cardiac malformations. Common mutations are rare in unrelated families. We analysed, by direct sequencing, the gene encoding NKX2–5 in the diseased heart tissues of 68 patients with complex congenital heart disease, focussing particularly on atrial, ventricular, and atrioventricular septal defects. We identified 35 non-synonymous NKX2–5 mutations in the diseased heart tissues of patients. These mutations were mainly absent in normal, for example, unaffected, heart tissue of the same patient, indicating the somatic nature and mosaicism of mutations. We also observed multiple mutations and multiple haplotypes, as well as mutations in Down’s syndrome patients with cardiac malformations. Taken collectively, the above results suggest the somatic nature of NKX2–5 mutations associated with complex cardiac malformations. Somatic mutations in transcription factor genes of cardiac progenitor cells provide a novel mechanism of disease.

Footnotes

  • Financial support to JB from the Lower Saxony Ministry of Science and Culture is greatly appreciated.

  • Conflict of interest: none declared.