Back to Search
Start Over
A New ISL1 Loss-of-Function Mutation Predisposes to Congenital Double Outlet Right Ventricle
- Source :
- International heart journal. 60(5)
- Publication Year :
- 2019
-
Abstract
- Occurring in about 1% of all live births, congenital heart defects (CHDs) represent the most frequent type of developmental abnormality and account for remarkably increased infant morbidity and mortality. Aggregating studies demonstrate that genetic components have a key role in the occurrence of CHDs. Nevertheless, due to pronounced genetic heterogeneity, the genetic causes of CHDs remain unclear in most patients. In this research, 114 unrelated patients affected with CHDs and 218 unrelated individuals without CHDs served as controls were recruited. The coding regions and splicing donors/acceptors of the ISL1 gene, which codes for a transcription factor required for proper cardiovascular development, were screened for mutations by sequencing in all study participants. The functional characteristics of an identified ISL1 mutation were delineated with a dual-luciferase reporter assay system. As a result, a new heterozygous ISL1 mutation, NM_002202.2: c.225CG; p. (Tyr75*), was discovered in an index patient with double outlet right ventricle and ventricular septal defect. Analysis of the proband's family unveiled that the mutation co-segregated with the CHD phenotype. The nonsense mutation was absent in the 436 control chromosomes. Biological analysis showed that the mutant ISL1 protein had no transcriptional activity. Furthermore, the mutation nullified the synergistic activation between ISL1 and TBX20, another CHD-associated transcription factor. This research for the first time links an ISL1 loss-of-function mutation to double outlet right ventricle in humans, which adds insight to the molecular pathogenesis underpinning CHDs, suggesting potential implications for timely personalized management of CHD patients.
- Subjects :
- Heart Defects, Congenital
Male
China
Heterozygote
Incidence
LIM-Homeodomain Proteins
Infant
Prognosis
Risk Assessment
Double Outlet Right Ventricle
Pedigree
Causality
Hospitals, University
Genes, Reporter
Loss of Function Mutation
Case-Control Studies
Child, Preschool
Mutation
Humans
Female
Genetic Predisposition to Disease
Retrospective Studies
Transcription Factors
Subjects
Details
- ISSN :
- 13493299
- Volume :
- 60
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- International heart journal
- Accession number :
- edsair.pmid..........cec7cd9afb4e312881624adf8410a68c