The c.1617del variant of TMEM260 is identified as the most frequent single gene determinant for Japanese patients with a specific type of congenital heart disease.

Autor: Inoue T; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.; Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan., Takase R; Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan., Uchida K; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan. keiuchid@keio.jp.; Keio University Health Center, Tokyo, Japan. keiuchid@keio.jp., Kodo K; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan., Suda K; Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan., Watanabe Y; Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan.; Research Institute of Medical Mass Spectrometry, Kurume University School of Medicine, Fukuoka, Japan., Yoshiura KI; Department of Human Genetics, Division of Advanced Preventive Medical Sciences, Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan., Kunimatsu M; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.; Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Japan., Ishizaki R; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan., Azuma K; Institute for Comprehensive Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan., Inai K; Department of Pediatric Cardiology and Adult Congenital Cardiology, Tokyo Women's Medical University, Tokyo, Japan., Muneuchi J; Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Kitakyushu, Japan., Furutani Y; Department of Pediatric Cardiology and Adult Congenital Cardiology, Tokyo Women's Medical University, Tokyo, Japan., Akagawa H; Institute for Comprehensive Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan., Yamagishi H; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.; Center for Preventive Medicine, Keio University School of Medicine, Tokyo, Japan.
Jazyk: angličtina
Zdroj: Journal of human genetics [J Hum Genet] 2024 May; Vol. 69 (5), pp. 215-222. Date of Electronic Publication: 2024 Feb 26.
DOI: 10.1038/s10038-024-01225-w
Abstrakt: Although the molecular mechanisms underlying congenital heart disease (CHD) remain poorly understood, recent advances in genetic analysis have facilitated the exploration of causative genes for CHD. We reported that the pathogenic variant c.1617del of TMEM260, which encodes a transmembrane protein, is highly associated with CHD, specifically persistent truncus arteriosus (PTA), the most severe cardiac outflow tract (OFT) defect. Using whole-exome sequencing, the c.1617del variant was identified in two siblings with PTA in a Japanese family and in three of the 26 DNAs obtained from Japanese individuals with PTA. The c.1617del of TMEM260 has been found only in East Asians, especially Japanese and Korean populations, and the frequency of this variant in PTA is estimated to be next to that of the 22q11.2 deletion, the most well-known genetic cause of PTA. Phenotype of patients with c.1617del appears to be predominantly in the heart, although TMEM260 is responsible for structural heart defects and renal anomalies syndrome (SHDRA). The mouse TMEM260 variant (p.W535Cfs*56), synonymous with the human variant (p.W539Cfs*9), exhibited truncation and downregulation by western blotting, and aggregation by immunocytochemistry. In situ hybridization demonstrated that Tmem260 is expressed ubiquitously during embryogenesis, including in the development of cardiac OFT implicated in PTA. This expression may be regulated by a ~ 0.8 kb genomic region in intron 3 of Tmem260 that includes multiple highly conserved binding sites for essential cardiac transcription factors, thus revealing that the c.1617del variant of TMEM260 is the major single-gene variant responsible for PTA in the Japanese population.
(© 2024. The Author(s).)
Databáze: MEDLINE
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