BACKGROUND: Mutations in transcription factor NKX2.5 cause congenital heart disease (CHD). We identified a CHD family with atrial septal defects (ASDs), atrioventricular block, ventricular noncompaction, syncope and sudden death. Our objective is to identify the disease-causing mutation in the CHD family. METHODS: Direct DNA sequence analysis was used to identify the CHD mutation. The functional effects of the mutation were characterized by a luciferase reporter assay and immunostaining. RESULTS: A novel, de novo 2-bp insertion (c.512insGC) was identified in exon 2 of NKX2.5. Mutation c.512insGC co-segregates with CHD in the family, and is not present in 200 controls. Functional studies indicate that the c.512insGC mutation impedes nuclear localization of NKX2.5 and causes a total loss of transactivation activity of NKX2.5. Furthermore, no NKX2.5 mutation was identified in 125 sporadic Chinese CHD patients. CONCLUSIONS: (1) NKX2.5 mutation c.512insGC is associated with ASDs, syncope and sudden death. It is the second de novo mutation identified in NKX2.5. (2) NKX2.5 mutations are rare in sporadic CHD patients. (3) This study for the first time identifies association between a NKX2.5 mutation and ventricular noncompaction. Our results significantly expand the phenotypic spectrum of NKX2.5 mutations.
BACKGROUND: Mutations in transcription factor NKX2.5 cause congenital heart disease (CHD). We identified a CHD family with atrial septal defects (ASDs), atrioventricular block, ventricular noncompaction, syncope and sudden death. Our objective is to identify the disease-causing mutation in the CHD family. METHODS: Direct DNA sequence analysis was used to identify the CHD mutation. The functional effects of the mutation were characterized by a luciferase reporter assay and immunostaining. RESULTS: A novel, de novo 2-bp insertion (c.512insGC) was identified in exon 2 of NKX2.5. Mutation c.512insGC co-segregates with CHD in the family, and is not present in 200 controls. Functional studies indicate that the c.512insGC mutation impedes nuclear localization of NKX2.5 and causes a total loss of transactivation activity of NKX2.5. Furthermore, no NKX2.5 mutation was identified in 125 sporadic Chinese CHD patients. CONCLUSIONS: (1) NKX2.5 mutation c.512insGC is associated with ASDs, syncope and sudden death. It is the second de novo mutation identified in NKX2.5. (2) NKX2.5 mutations are rare in sporadic CHD patients. (3) This study for the first time identifies association between a NKX2.5 mutation and ventricular noncompaction. Our results significantly expand the phenotypic spectrum of NKX2.5 mutations.
Authors: B G Bruneau; G Nemer; J P Schmitt; F Charron; L Robitaille; S Caron; D A Conner; M Gessler; M Nemer; C E Seidman; J G Seidman Journal: Cell Date: 2001-09-21 Impact factor: 41.582
Authors: David A Elliott; Edwin P Kirk; Thomas Yeoh; Suchitra Chandar; Fiona McKenzie; Peter Taylor; Paul Grossfeld; Diane Fatkin; Owen Jones; Peter Hayes; Michael Feneley; Richard P Harvey Journal: J Am Coll Cardiol Date: 2003-06-04 Impact factor: 24.094
Authors: Gasnat Shaboodien; Timothy F Spracklen; Stephen Kamuli; Polycarp Ndibangwi; Carla Van Niekerk; Ntobeko A B Ntusi Journal: Cardiovasc Diagn Ther Date: 2020-04
Authors: Milena B Furtado; Julia C Wilmanns; Anjana Chandran; Joelle Perera; Olivia Hon; Christine Biben; Taylor J Willow; Hieu T Nim; Gurpreet Kaur; Stephanie Simonds; Qizhu Wu; David Willians; Ekaterina Salimova; Nicolas Plachta; James M Denegre; Stephen A Murray; Diane Fatkin; Michael Cowley; James T Pearson; David Kaye; Mirana Ramialison; Richard P Harvey; Nadia A Rosenthal; Mauro W Costa Journal: JCI Insight Date: 2017-03-23