A New <i>ISL1</i> Loss-of-Function Mutation Predisposes to Congenital Double Outlet Right Ventricle
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- Wang Zhi
- Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine
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- Song Hao-Ming
- Department of Cardiology, Tongji Hospital, Tongji University School of Medicine
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- Wang Fei
- Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine
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- Zhao Cui-Mei
- Department of Cardiology, Tongji Hospital, Tongji University School of Medicine
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- Huang Ri-Tai
- Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University
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- Xue Song
- Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University
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- Li Ruo-Gu
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University
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- Qiu Xing-Biao
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University
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- Xu Ying-Jia
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University
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- Liu Xing-Yuan
- Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine
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- Yang Yi-Qing
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University Department of Cardiovascular Research Laboratory, The Fifth People's Hospital of Shanghai, Fudan University Department of Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University
抄録
<p>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.</p>
収録刊行物
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- International Heart Journal
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International Heart Journal 60 (5), 1113-1122, 2019-09-27
一般社団法人 インターナショナル・ハート・ジャーナル刊行会