Shoichiro Kanda1,2, Masaki Ohmuraya3, Hiroyuki Akagawa4, Shigeru Horita5, Yasuhiro Yoshida6, Naoto Kaneko2, Noriko Sugawara2, Kiyonobu Ishizuka2, Kenichiro Miura2, Yutaka Harita6, Toshiyuki Yamamoto4,7, Akira Oka6, Kimi Araki8, Toru Furukawa4,9, Motoshi Hattori2. 1. Department of Pediatrics, The University of Tokyo, Tokyo, Japan; skanda-tky@umin.ac.jp. 2. Department of Pediatric Nephrology. 3. Department of Genetics, Hyogo College of Medicine, Hyogo, Japan. 4. Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo, Japan. 5. Department of Pathology, Kidney Center, School of Medicine, and. 6. Department of Pediatrics, The University of Tokyo, Tokyo, Japan. 7. Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan. 8. Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan; and. 9. Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Abstract
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.
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.
Authors: David Grote; Sami Kamel Boualia; Abdallah Souabni; Calli Merkel; Xuan Chi; Frank Costantini; Thomas Carroll; Maxime Bouchard Journal: PLoS Genet Date: 2008-12-26 Impact factor: 5.917
Authors: Daw-Yang Hwang; Gabriel C Dworschak; Stefan Kohl; Pawaree Saisawat; Asaf Vivante; Alina C Hilger; Heiko M Reutter; Neveen A Soliman; Radovan Bogdanovic; Elijah O Kehinde; Velibor Tasic; Friedhelm Hildebrandt Journal: Kidney Int Date: 2014-01-15 Impact factor: 10.612