RGD Reference Report - A New ISL1 Loss-of-Function Mutation Predisposes to Congenital Double Outlet Right Ventricle. - Rat Genome Database

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A New ISL1 Loss-of-Function Mutation Predisposes to Congenital Double Outlet Right Ventricle.

Authors: Wang, Zhi  Song, Hao-Ming  Wang, Fei  Zhao, Cui-Mei  Huang, Ri-Tai  Xue, Song  Li, Ruo-Gu  Qiu, Xing-Biao  Xu, Ying-Jia  Liu, Xing-Yuan  Yang, Yi-Qing 
Citation: Wang Z, etal., Int Heart J. 2019 Sep 27;60(5):1113-1122. doi: 10.1536/ihj.18-685. Epub 2019 Sep 4.
RGD ID: 243048467
Pubmed: PMID:31484864   (View Abstract at PubMed)
DOI: DOI:10.1536/ihj.18-685   (Journal Full-text)

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.225C>G; 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ISL1Humandouble outlet right ventricle  IAGP DNA:mutation:cds:c.225C>G(human)RGD 
Isl1Ratdouble outlet right ventricle  ISOISL1 (Homo sapiens)DNA:mutation:cds:c.225C>G(human)RGD 
Isl1Mousedouble outlet right ventricle  ISOISL1 (Homo sapiens)DNA:mutation:cds:c.225C>G(human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Isl1  (ISL LIM homeobox 1)

Genes (Mus musculus)
Isl1  (ISL1 transcription factor, LIM/homeodomain)

Genes (Homo sapiens)
ISL1  (ISL LIM homeobox 1)

Additional Information