ハツトリ　モトシ   Hatsutori Motoshi   服部　元史    所属   医学部 医学科（東京女子医科大学病院）    職種   非常勤嘱託
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Deletion in the Cobalamin Synthetase W Domain-Containing Protein 1 Gene Is associated with Congenital Anomalies of the Kidney and Urinary Tract.
掲載誌名	正式名：Journal of the American Society of Nephrology : JASN 略　 称：J Am Soc Nephrol ISSNコード：15333450/10466673
掲載区分	国外
巻・号・頁	31(1),pp.139-147
著者・共著者	Kanda Shoichiro, Ohmuraya Masaki, Akagawa Hiroyuki, Horita Shigeru, Yoshida Yasuhiro, Kaneko Naoto, Sugawara Noriko, Ishizuka Kiyonobu, Miura Kenichiro, Harita Yutaka, Yamamoto Toshiyuki, Oka Akira, Araki Kimi, Furukawa Toru, Hattori Motoshi
発行年月	2020/01
概要	BACKGROUND:Researchers have identified about 40 genes with mutations that result in the most common cause of CKD in children, congenital anomalies of the kidney and urinary tract (CAKUT), but approximately 85% of patients with CAKUT lack mutations in these genes. The anomalies that comprise CAKUT are clinically heterogenous, and thought to be caused by disturbances at different points in kidney development. However, identification of novel CAKUT-causing genes remains difficult because of their variable expressivity, incomplete penetrance, and heterogeneity.METHODS:We investigated two generations of a family that included two siblings with CAKUT. Although the parents and another child were healthy, the two affected siblings presented the same manifestations, unilateral renal agenesis and contralateral renal hypoplasia. To search for a novel causative gene of CAKUT, we performed whole-exome and whole-genome sequencing of DNA from the family members. We also generated two lines of genetically modified mice with a gene deletion present only in the affected siblings, and performed immunohistochemical and phenotypic analyses of these mice.RESULTS:We found that the affected siblings, but not healthy family members, had a homozygous deletion in the Cobalamin Synthetase W Domain-Containing Protein 1 (CBWD1) gene. Whole-genome sequencing uncovered genomic breakpoints, which involved exon 1 of CBWD1, harboring the initiating codon. Immunohistochemical analysis revealed high expression of Cbwd1 in the nuclei of the ureteric bud cells in the developing kidneys. Cbwd1-deficient mice showed CAKUT phenotypes, including hydronephrosis, hydroureters, and duplicated ureters.CONCLUSIONS:The identification of a deletion in CBWD1 gene in two siblings with CAKUT implies a role for CBWD1 in the etiology of some cases of CAKUT.
DOI	10.1681/ASN.2019040398
PMID	31862704