title: Novel NKX2-5 mutations in diseased heart tissues of patients with cardiac malformations.
abstract: NKX2-5 is a homeodomain-containing transcription factor important in cardiac development. Familial mutations in the NKX2-5 gene are associated with cardiac abnormalities, but mutations are rare in sporadic cases. We studied the pathology and molecular genetics of NKX2-5 in diseased heart tissues of 68 patients with complex congenital heart disease (CHD), particularly atrial (ASD), ventricular (VSD), and atrioventricular septal defects (AVSD). We also studied DNA extracted from 16 normal hearts, as well as lymphocytic DNA from 50 healthy volunteers, 7 families, and 4 unrelated individuals with CHD. Direct sequencing revealed 53 NKX2-5 mutations in the diseased heart tissues, including nonsynonymous substitutions in the homeodomain of NKX2-5. We found common mutations among unrelated patients, but certain mutations were specific to VSDs and AVSDs. Many patients had multiple NKX2-5 mutations, up to 14 nonsynonymous mutations per patient in VSDs. Importantly, these nonsynonymous mutations were mainly absent in normal heart tissues of the same CHD patients, thus indicating somatic origin and mosaicism of mutations. Further, observed mutations were completely absent in normal hearts and lymphocytic DNA of healthy individuals. Our findings provide new insights for somatic NKX2-5 mutations to be of importance in congenital heart disease.
authors.affiliation: Department of Drug Research and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.
authors.forename: Stella Marie
authors.initials: SM
authors.lastname: Reamon-Buettner
authors.forename: Hartmut
authors.initials: H
authors.lastname: Hecker
authors.forename: Katharina
authors.initials: K
authors.lastname: Spanel-Borowski
authors.forename: Steffen
authors.initials: S
authors.lastname: Craatz
authors.forename: Eberhard
authors.initials: E
authors.lastname: Kuenzel
authors.forename: Juergen
authors.initials: J
authors.lastname: Borlak
mesh_terms: D001483:Base Sequence; D016000:Cluster Analysis; D017931:DNA Primers; D005091:Exons / Q000235:genetics; D006321:Heart / Q000502:physiology; D006330:Heart Defects, Congenital / Q000235:genetics*; D006331:Heart Diseases / Q000235:genetics; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D012016:Reference Values; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D017931:DNA Primers; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D014157:Transcription Factors