RGD Reference Report - ISL1 loss-of-function variation causes familial atrial fibrillation. - Rat Genome Database

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ISL1 loss-of-function variation causes familial atrial fibrillation.

Authors: Wu, Shao-Hui  Wang, Xin-Hua  Xu, Ying-Jia  Gu, Jia-Ning  Yang, Chen-Xi  Qiao, Qi  Guo, Xiao-Juan  Guo, Yu-Han  Qiu, Xing-Biao  Jiang, Wei-Feng  Yang, Yi-Qing 
Citation: Wu SH, etal., Eur J Med Genet. 2020 Nov;63(11):104029. doi: 10.1016/j.ejmg.2020.104029. Epub 2020 Aug 6.
RGD ID: 243049245
Pubmed: PMID:32771629   (View Abstract at PubMed)
DOI: DOI:10.1016/j.ejmg.2020.104029   (Journal Full-text)

Atrial fibrillation (AF) represents the most frequent form of sustained cardiac rhythm disturbance, affecting approximately 1% of the general population worldwide, and confers a substantially enhanced risk of cerebral stroke, heart failure, and death. Increasing epidemiological studies have clearly demonstrated a strong genetic basis for AF, and variants in a wide range of genes, including those coding for ion channels, gap junction channels, cardiac structural proteins and transcription factors, have been identified to underlie AF. Nevertheless, the genetic pathogenesis of AF is complex and still far from completely understood. Here, whole-exome sequencing and bioinformatics analyses of a three-generation family with AF were performed, and after filtering variants by multiple metrics, we identified a heterozygous variant in the ISL1 gene (encoding a transcription factor critical for embryonic cardiogenesis and postnatal cardiac remodeling), NM_002202.2: c.481G > T; p.(Glu161*), which was validated by Sanger sequencing and segregated with autosome-dominant AF in the family with complete penetrance. The nonsense variant was absent from 284 unrelated healthy individuals used as controls. Functional assays with a dual-luciferase reporter assay system revealed that the truncating ISL1 protein lost transcriptional activation on the verified target genes MEF2C and NKX2-5. Additionally, the variant nullified the synergistic transactivation between ISL1 and TBX5 as well as GATA4, two other transcription factors that have been implicated in AF. The findings suggest ISL1 as a novel gene contributing to AF, which adds new insight to the genetic mechanisms underpinning AF, implying potential implications for genetic testing and risk stratification of the AF family members.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ISL1Humanatrial fibrillation  IAGP DNA:mutation:cds:c.481G>T (human)RGD 
Isl1Ratatrial fibrillation  ISOISL1 (Homo sapiens)DNA:mutation:cds:c.481G>T (human)RGD 
Isl1Mouseatrial fibrillation  ISOISL1 (Homo sapiens)DNA:mutation:cds:c.481G>T (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