HATTORI Motoshi    Department   School of Medicine(Tokyo Women's Medical University Hospital), School of Medicine    Position   Professor
Article types	Original article
Language	English
Peer review	Peer reviewed
Title	Deletion in the Cobalamin Synthetase W Domain-Containing Protein 1 Gene Is associated with Congenital Anomalies of the Kidney and Urinary Tract.
Journal	Formal name：Journal of the American Society of Nephrology : JASN Abbreviation：J Am Soc Nephrol ISSN code：15333450/10466673
Domestic / Foregin	Foregin
Volume, Issue, Page	31(1),pp.139-147
Author and coauthor	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
Publication date	2020/01
Summary	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