Genetic Variants in ARHGEF6 Cause Congenital Anomalies of the Kidneys and Urinary Tract in Humans, Mice, and Frogs.

Autor:	Klämbt V; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité Universitätsmedizin Berlin, Berlin, Germany.; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin, Germany., Buerger F; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Wang C; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Nephrology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China., Naert T; Institute of Anatomy, Faculty of Medicine, University of Zurich, Zurich, Switzerland., Richter K; Institute for Biochemistry and Cell Biology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany., Nauth T; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Weiss AC; Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany., Sieckmann T; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Translatationale Physiologie, Berlin, Germany., Lai E; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Connaughton DM; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Seltzsam S; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Mann N; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Majmundar AJ; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Wu CW; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.; Departments of Genetics and Urology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio., Onuchic-Whitford AC; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.; Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Shril S; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Schneider S; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Schierbaum L; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Dai R; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Bekheirnia MR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas., Joosten M; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands., Shlomovitz O; Department of Pediatrics B, Edmond and Lily Safra Children's Hospital, Sackler Faculty of Medicine, Sheba Medical Center, Tel-Hashomer, Israel.; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel., Vivante A; Department of Pediatrics B, Edmond and Lily Safra Children's Hospital, Sackler Faculty of Medicine, Sheba Medical Center, Tel-Hashomer, Israel., Banne E; The Genetics Institute, Kaplan Medical Center-Rehovot, Hebrew University and Hadassah Medical School, Jerusalem, Israel., Mane S; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.; Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, Connecticut., Lifton RP; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.; Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, Connecticut.; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, New York., Kirschner KM; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Translatationale Physiologie, Berlin, Germany., Kispert A; Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany., Rosenberger G; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Fischer KD; Institute for Biochemistry and Cell Biology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany., Lienkamp SS; Institute of Anatomy, Faculty of Medicine, University of Zurich, Zurich, Switzerland., Zegers MMP; Department of Cell Biology, Radboud University Medical Center, Nijmegen, The Netherlands., Hildebrandt F; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2023 Feb 01; Vol. 34 (2), pp. 273-290. Date of Electronic Publication: 2023 Nov 22.
DOI:	10.1681/ASN.2022010050
Abstrakt:	Background: About 40 disease genes have been described to date for isolated CAKUT, the most common cause of childhood CKD. However, these genes account for only 20% of cases. ARHGEF6, a guanine nucleotide exchange factor that is implicated in biologic processes such as cell migration and focal adhesion, acts downstream of integrin-linked kinase (ILK) and parvin proteins. A genetic variant of ILK that causes murine renal agenesis abrogates the interaction of ILK with a murine focal adhesion protein encoded by Parva , leading to CAKUT in mice with this variant. Methods: To identify novel genes that, when mutated, result in CAKUT, we performed exome sequencing in an international cohort of 1265 families with CAKUT. We also assessed the effects in vitro of wild-type and mutant ARHGEF6 proteins, and the effects of Arhgef6 deficiency in mouse and frog models. Results: We detected six different hemizygous variants in the gene ARHGEF6 (which is located on the X chromosome in humans) in eight individuals from six families with CAKUT. In kidney cells, overexpression of wild-type ARHGEF6 -but not proband-derived mutant ARHGEF6 -increased active levels of CDC42/RAC1, induced lamellipodia formation, and stimulated PARVA-dependent cell spreading. ARHGEF6-mutant proteins showed loss of interaction with PARVA. Three-dimensional Madin-Darby canine kidney cell cultures expressing ARHGEF6-mutant proteins exhibited reduced lumen formation and polarity defects. Arhgef6 deficiency in mouse and frog models recapitulated features of human CAKUT. Conclusions: Deleterious variants in ARHGEF6 may cause dysregulation of integrin-parvin-RAC1/CDC42 signaling, thereby leading to X-linked CAKUT. (Copyright © 2022 by the American Society of Nephrology.)
Databáze:	MEDLINE
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