AKAGAWA HIROYUKI    Department   Research Institutes and Facilities, Research Institutes and Facilities    Position   Associate Professor
Article types	Original article
Language	English
Peer review	Peer reviewed
Title	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.
Journal	Formal name：Journal of human genetics Abbreviation：J Hum Genet ISSN code：1435232X/14345161
Domestic / Foregin	Foregin
Volume, Issue, Page	Online ahead of print,pp.*-*
Author and coauthor	Inoue Tadashi, Takase Ryuta, Uchida Keiko, Kodo Kazuki, Suda Kenji, Watanabe Yoriko, Yoshiura Koh-Ichiro, Kunimatsu Masaya, Ishizaki Reina, Azuma Kenko, Inai Kei, Muneuchi Jun, Furutani Yoshiyuki, Akagawa Hiroyuki, Yamagishi Hiroyuki
Publication date	2024/02
Summary	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.
DOI	10.1038/s10038-024-01225-w
PMID	38409496