Genetic variations of ISL1 associated with human congenital heart disease in Chinese Han people

Luo, Zhengrong; Sun, Huichao; Yang, Ze; Ma, Yanlin; Gu, Yifan; He, Yuefeng; Wei, Duo; Xia, Lang; Yang, Bicheng; Guo, Tong

doi:10.4238/2014.february.28.5

Cited by 12 publications

(8 citation statements)

References 24 publications

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“…121) Previous studies demonstrated that several common polymorphisms in the ISL1 gene conferred an enhanced susceptibility to CHDs. 114,115) Stevens and coworkers 114) performed a case-control study of the 30 polymorphisms located at the ISL1 locus in 300 pediatric cases affected with complex CHDs and 2,201 healthy control children and found that 8 polymorphisms (rs6449612, rs6449600, rs4865656, rs2115322, IVS1+17C>T, rs6869844, rs1017, rs6867206) in and near ISL1 were significantly associated with enhanced vulnerability to CHDs. In order to independently verify the above-mentioned results, they made a replication research of these genetic polymorphisms in 1,044 new patients and 3,934 independent control individuals and validated the significant association of these polymorphisms with increased susceptibility to nonsyndromic CHDs.…”

Section: Discussionmentioning

confidence: 99%

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A New <i>ISL1</i> Loss-of-Function Mutation Predisposes to Congenital Double Outlet Right Ventricle

et al. 2019

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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. (Int Heart J 2019; 60: 1113-1122

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Section: Discussionmentioning

confidence: 99%

“…110) In humans, multiple variants in ISL1 have been reported to confer an enhanced vulnerability to CHDs in diverse cohorts of patients. [114][115][116] These results make it justifiable to scan ISL1 for mutations underlying CHDs in another cohort of patients.…”

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confidence: 96%

A New <i>ISL1</i> Loss-of-Function Mutation Predisposes to Congenital Double Outlet Right Ventricle

et al. 2019

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“…In addition, we found that both phenotypes are not linked, and that the cardiac phenotype is associated with a novel mutation in the gene encoding CSRP1. This is the second gene encoding a LIM protein shown to be implicated in CHD after ISL1 (Stevens et al, 2010 ; Luo et al, 2014 ). In addition, we interrogated the penetrance of this mutation by searching for potential modifiers.…”

Section: Discussionmentioning

confidence: 99%

A Novel Role for CSRP1 in a Lebanese Family with Congenital Cardiac Defects

et al. 2017

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Despite an obvious role for consanguinity in congenital heart disease (CHD), most studies fail to document a monogenic model of inheritance except for few cases. We hereby describe a first-degree cousins consanguineous Lebanese family with 7 conceived children: 2 died in utero of unknown causes, 3 have CHD, and 4 have polydactyly. The aim of the study is to unveil the genetic variant(s) causing these phenotypes using next generation sequencing (NGS) technology. Targeted exome sequencing identified a heterozygous duplication in CSRP1 which leads to a potential frameshift mutation at position 154 of the protein. This mutation is inherited from the father, and segregates only with the CHD phenotype. The in vitro characterization demonstrates that the mutation dramatically abrogates its transcriptional activity over cardiac promoters like NPPA. In addition, it differentially inhibits the physical association of CSRP1 with SRF, GATA4, and with the newly described partner herein TBX5. Whole exome sequencing failed to show any potential variant linked to polydactyly, but revealed a novel missense mutation in TRPS1. This mutation is inherited from the healthy mother, and segregating only with the cardiac phenotype. Both TRPS1 and CSRP1 physically interact, and the mutations in each abrogate their partnership. Our findings add fundamental knowledge into the molecular basis of CHD, and propose the di-genic model of inheritance as responsible for such malformations.

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“…ISL1 rs1017 is one of the most frequently reported ISL1 variants; however, its correlation with CHD remains controversial. ISL1 rs1017 was reported to be related to the risk of CHD in a white population (Stevens et al, 2010) and a Chinese cohort (Luo et al, 2014), while the other studies showed opposite results (Xue et al, 2012;Cresci et al, 2013). Moreover, ISL1 haploinsufficiency was shown to be associated with d-transposition of the great arteries (d-TGA) (Osoegawa et al, 2014).…”

Section: Islet1 and Congenital Heart Diseasesmentioning

confidence: 99%

Spotlight on Isl1: A Key Player in Cardiovascular Development and Diseases

Ren

Miao

et al. 2021

Front. Cell Dev. Biol.

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Cardiac transcription factors orchestrate a regulatory network controlling cardiovascular development. Isl1, a LIM-homeodomain transcription factor, acts as a key player in multiple organs during embryonic development. Its crucial roles in cardiovascular development have been elucidated by extensive studies, especially as a marker gene for the second heart field progenitors. Here, we summarize the roles of Isl1 in cardiovascular development and function, and outline its cellular and molecular modes of action, thus providing insights for the molecular basis of cardiovascular diseases.

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Genetic variations of ISL1 associated with human congenital heart disease in Chinese Han people

Cited by 12 publications

References 24 publications

A New <i>ISL1</i> Loss-of-Function Mutation Predisposes to Congenital Double Outlet Right Ventricle

A New <i>ISL1</i> Loss-of-Function Mutation Predisposes to Congenital Double Outlet Right Ventricle

A Novel Role for CSRP1 in a Lebanese Family with Congenital Cardiac Defects

Spotlight on Isl1: A Key Player in Cardiovascular Development and Diseases

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