RESUMEN
The genetic alterations leading to congenital heart defects (CHD) are still poorly understood. We and others have recently shown that in mice loss of Hey2 results in a high incidence of fatal ventricular and atrial septal defects, combined with tricuspid stenosis or atresia in some cases. The phenotype has been postulated to resemble human tetralogy of Fallot. Our analysis of CD1 outbred mice suggests that phenotypic consequences of Hey2 loss can be quite variable and dependent on modifier genes as we detected only isolated VSDs with lower prevalence and a significantly reduced mortality rate in this strain. Since Hey2 is one of the few Notch target genes, it is also conceivable that HEY2 mutations may account for cases of Alagille syndrome (AGS: variable combinations of heart, skeleton, eye, and facial malformations and cholestasis), in which the typical mutations of the Notch ligand JAG1 cannot be found. To clarify the role of HEY2 in human CHD and AGS, we screened by direct sequencing 23 children with CHD and 38 patients diagnosed with AGS, which lack mutations in the JAG1 gene. We found two types of silent changes in the coding region: a CTT-->CTG transition in exon 3 and a CTG-->CTC polymorphism in exon 5. Furthermore, a heterozygous SNP in the splice donor site of exon 4 was detected that is unlikely to disrupt splicing. Although the high incidence and variability of human congenital heart defects implies a multifactorial genetic basis, our results suggest that mutation of HEY2 is not a major contributing factor.
Asunto(s)
Síndrome de Alagille/genética , Cardiopatías Congénitas/genética , Proteínas Represoras/genética , Adolescente , Síndrome de Alagille/patología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Proteínas de Unión al Calcio , Niño , Preescolar , ADN/química , ADN/genética , Cardiopatías Congénitas/patología , Humanos , Lactante , Péptidos y Proteínas de Señalización Intercelular , Proteína Jagged-1 , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Repeticiones de Microsatélite/genética , Mutación Puntual , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Proteínas Serrate-JaggedRESUMEN
The long-QT syndrome (LQTS) is a familiar disease characterized by abnormal myocardial repolarization and a high risk of sudden cardiac death. As a hallmark of the disease, the heart-rate corrected QT interval is intrinsically prolonged. Recent advances in molecular genetics have elicited that various inborn defects in cardiac ion channel genes regulating cardiac ion currents underlie this propensity to develop malignant ventricular arrhythmias. Meanwhile, a widespread locus and allelic genetic heterogeneity in LQTS is evident, thus, complicating the power of DNA diagnostic tools. The following review will briefly summarize clinical and genetic aspects of LQTS.