RESUMEN
Congenital heart defects (CHD) are collectively the most common form of congenital malformation. Studies of human cases and animal models have revealed that mutations in several genes are responsible for both familial and sporadic forms of CHD. We have previously shown that a mutation in MYH6 can cause an autosomal dominant form of atrial septal defect (ASD), whereas others have identified mutations of the same gene in patients with hypertrophic and dilated cardiomyopathy. In the present study, we report a mutation analysis of MYH6 in patients with a wide spectrum of sporadic CHD. The mutation analysis of MYH6 was performed in DNA samples from 470 cases of isolated CHD using denaturing high-performance liquid chromatography and sequence analysis to detect point mutations and small deletions or insertions, and multiplex amplifiable probe hybridization to detect partial or complete copy number variations. One non-sense mutation, one splicing site mutation and seven non-synonymous coding mutations were identified. Transfection of plasmids encoding mutant and non-mutant green fluorescent protein-MYH6 fusion proteins in mouse myoblasts revealed that the mutations A230P and A1366D significantly disrupt myofibril formation, whereas the H252Q mutation significantly enhances myofibril assembly in comparison with the non-mutant protein. Our data indicate that functional variants of MYH6 are associated with cardiac malformations in addition to ASD and provide a novel potential mechanism. Such phenotypic heterogeneity has been observed in other genes mutated in CHD.
Asunto(s)
Miosinas Cardíacas/genética , Cardiopatías Congénitas/genética , Defectos del Tabique Interatrial/genética , Miofibrillas/metabolismo , Cadenas Pesadas de Miosina/genética , Animales , Miosinas Cardíacas/metabolismo , Cardiomiopatía Dilatada/genética , Cromatografía Líquida de Alta Presión , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Estudios de Asociación Genética , Humanos , Ratones , Mutación , Mioblastos/citología , Miofibrillas/genética , Cadenas Pesadas de Miosina/metabolismo , Plásmidos , TransfecciónRESUMEN
A novel interaction between GATA4 and TBX5 could explain phenotypic similarities (atrial septal defects) between patients with mutations in GATA4 or TBX5. The cardiac transcription factor GATA4 has not previously been implicated in a human disorder but a recent paper by Garg et al. provides evidence of mutations in GATA4 that cause atrial septal defects. Mutations in TBX5 have already been shown to cause similar atrial septal defects in Holt-Oram syndrome.