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

Humans Mice Animals Dogs Urogenital Abnormalities / genetics Kidney / abnormalities Urinary Tract / abnormalities Integrins / metabolism Mutant Proteins / metabolism Rho Guanine Nucleotide Exchange Factors / genetics

Journal

Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836

Informations de publication

Date de publication:
01 02 2023
Historique:
received: 27 01 2022
accepted: 08 11 2022
pmc-release: 01 02 2024
pubmed: 23 11 2022
medline: 8 2 2023
entrez: 22 11 2022
Statut: ppublish

Résumé

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. 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. 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. Deleterious variants in ARHGEF6 may cause dysregulation of integrin-parvin-RAC1/CDC42 signaling, thereby leading to X-linked CAKUT.

Sections du résumé

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.

Identifiants

DOI: 10.1681/ASN.2022010050 PMID: 36414417 PMC: PMC10103091
pubmed: 36414417
pii: 00001751-202302000-00014
doi: 10.1681/ASN.2022010050
pmc: PMC10103091
doi:

Substances chimiques

Integrins 0
Mutant Proteins 0
Arhgef6 protein, mouse 0
Rho Guanine Nucleotide Exchange Factors 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

273-290

Subventions

Organisme : NIDDK NIH HHS
ID : K08 DK125768
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006504
Pays : United States
Organisme : NICHD NIH HHS
ID : K12 HD052896
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK076683
Pays : United States
Organisme : NIDDK NIH HHS
ID : F32 DK122766
Pays : United States
Organisme : NHGRI NIH HHS
ID : U24 HG008956
Pays : United States

Informations de copyright

Copyright © 2022 by the American Society of Nephrology.

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Auteurs

Verena 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.

Florian Buerger (F)

Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Chunyan 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.

Thomas Naert (T)

Institute of Anatomy, Faculty of Medicine, University of Zurich, Zurich, Switzerland.

Karin Richter (K)

Institute for Biochemistry and Cell Biology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.

Theresa Nauth (T)

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Anna-Carina Weiss (AC)

Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany.

Tobias Sieckmann (T)

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Translatationale Physiologie, Berlin, Germany.

Ethan Lai (E)

Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Dervla M Connaughton (DM)

Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Steve Seltzsam (S)

Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Nina Mann (N)

Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Amar J Majmundar (AJ)

Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Chen-Han W 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.

Ana C 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.

Shirlee Shril (S)

Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Sophia Schneider (S)

Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Luca Schierbaum (L)

Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Rufeng Dai (R)

Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Mir Reza Bekheirnia (MR)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Marieke Joosten (M)

Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Omer 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.

Asaf Vivante (A)

Department of Pediatrics B, Edmond and Lily Safra Children's Hospital, Sackler Faculty of Medicine, Sheba Medical Center, Tel-Hashomer, Israel.

Ehud Banne (E)

The Genetics Institute, Kaplan Medical Center-Rehovot, Hebrew University and Hadassah Medical School, Jerusalem, Israel.

Shrikant 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.

Richard P 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.

Karin M Kirschner (KM)

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Translatationale Physiologie, Berlin, Germany.

Andreas Kispert (A)

Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany.

Georg Rosenberger (G)

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Klaus-Dieter Fischer (KD)

Institute for Biochemistry and Cell Biology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.

Soeren S Lienkamp (SS)

Institute of Anatomy, Faculty of Medicine, University of Zurich, Zurich, Switzerland.

Mirjam M P Zegers (MMP)

Department of Cell Biology, Radboud University Medical Center, Nijmegen, The Netherlands.

Friedhelm Hildebrandt (F)

Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

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Classifications MeSH

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Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Genetic Variants in ARHGEF6 Cause Congenital...
Recherchemedicale.com › Eucaryotes › Animaux › Genetic Variants in ARHGEF6 Cause Congenital...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Carnivora › Pinnipedia › Canidae › Chiens › Genetic Variants in ARHGEF6 Cause Congenital...
Recherchemedicale.com › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations urogénitales › Genetic Variants in ARHGEF6 Cause Congenital...
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Recherchemedicale.com › Appareil urogénital › Voies urinaires › Genetic Variants in ARHGEF6 Cause Congenital...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Intégrines › Genetic Variants in ARHGEF6 Cause Congenital...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines mutantes › Genetic Variants in ARHGEF6 Cause Congenital...
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