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

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Genetic Variants in ARHGEF6 Cause Congenital Anomalies of the Kidneys and Urinary Tract in Humans, Mice, and Frogs. / Klämbt, Verena; Buerger, Florian; Wang, Chunyan; Naert, Thomas; Richter, Karin; Nauth, Theresa; Weiss, Anna-Carina; Sieckmann, Tobias; Lai, Ethan; Connaughton, Dervla; Seltzsam, Steve; Mann, Nina; Majmundar, Amar; Wu, Chen-Han; Onuchic-Whitford, Ana; Shril, Shirlee; Schneider, Sophia; Schierbaum, Luca; Dai, Rufeng; Bekheirnia, Mir Reza; Joosten, Marieke; Shlomovitz, Omer; Vivante, Asaf; Banne, Ehud; Mane, Shrikant; Lifton, Richard P; Kirschner, Karin; Kispert, Andreas; Rosenberger, Georg; Fischer, Klaus-Dieter; Lienkamp, Soeren; Zegers, Mirjam; Hildebrandt, Friedhelm.

In: J AM SOC NEPHROL, Vol. 34, No. 2, 01.02.2023, p. 273-290.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Klämbt, V, Buerger, F, Wang, C, Naert, T, Richter, K, Nauth, T, Weiss, A-C, Sieckmann, T, Lai, E, Connaughton, D, Seltzsam, S, Mann, N, Majmundar, A, Wu, C-H, Onuchic-Whitford, A, Shril, S, Schneider, S, Schierbaum, L, Dai, R, Bekheirnia, MR, Joosten, M, Shlomovitz, O, Vivante, A, Banne, E, Mane, S, Lifton, RP, Kirschner, K, Kispert, A, Rosenberger, G, Fischer, K-D, Lienkamp, S, Zegers, M & Hildebrandt, F 2023, 'Genetic Variants in ARHGEF6 Cause Congenital Anomalies of the Kidneys and Urinary Tract in Humans, Mice, and Frogs', J AM SOC NEPHROL, vol. 34, no. 2, pp. 273-290. https://doi.org/10.1681/ASN.2022010050

APA

Klämbt, V., Buerger, F., Wang, C., Naert, T., Richter, K., Nauth, T., Weiss, A-C., Sieckmann, T., Lai, E., Connaughton, D., Seltzsam, S., Mann, N., Majmundar, A., Wu, C-H., Onuchic-Whitford, A., Shril, S., Schneider, S., Schierbaum, L., Dai, R., ... Hildebrandt, F. (2023). Genetic Variants in ARHGEF6 Cause Congenital Anomalies of the Kidneys and Urinary Tract in Humans, Mice, and Frogs. J AM SOC NEPHROL, 34(2), 273-290. https://doi.org/10.1681/ASN.2022010050

Vancouver

Klämbt V, Buerger F, Wang C, Naert T, Richter K, Nauth T et al. Genetic Variants in ARHGEF6 Cause Congenital Anomalies of the Kidneys and Urinary Tract in Humans, Mice, and Frogs. J AM SOC NEPHROL. 2023 Feb 1;34(2):273-290. https://doi.org/10.1681/ASN.2022010050

Bibtex

@article{2537622df9ff43139c2eb7f2ff032547,
title = "Genetic Variants in ARHGEF6 Cause Congenital Anomalies of the Kidneys and Urinary Tract in Humans, Mice, and Frogs",
abstract = "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.",
author = "Verena Kl{\"a}mbt and Florian Buerger and Chunyan Wang and Thomas Naert and Karin Richter and Theresa Nauth and Anna-Carina Weiss and Tobias Sieckmann and Ethan Lai and Dervla Connaughton and Steve Seltzsam and Nina Mann and Amar Majmundar and Chen-Han Wu and Ana Onuchic-Whitford and Shirlee Shril and Sophia Schneider and Luca Schierbaum and Rufeng Dai and Bekheirnia, {Mir Reza} and Marieke Joosten and Omer Shlomovitz and Asaf Vivante and Ehud Banne and Shrikant Mane and Lifton, {Richard P} and Karin Kirschner and Andreas Kispert and Georg Rosenberger and Klaus-Dieter Fischer and Soeren Lienkamp and Mirjam Zegers and Friedhelm Hildebrandt",
year = "2023",
month = feb,
day = "1",
doi = "10.1681/ASN.2022010050",
language = "English",
volume = "34",
pages = "273--290",
journal = "J AM SOC NEPHROL",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "2",

}

RIS

TY - JOUR

T1 - Genetic Variants in ARHGEF6 Cause Congenital Anomalies of the Kidneys and Urinary Tract in Humans, Mice, and Frogs

AU - Klämbt, Verena

AU - Buerger, Florian

AU - Wang, Chunyan

AU - Naert, Thomas

AU - Richter, Karin

AU - Nauth, Theresa

AU - Weiss, Anna-Carina

AU - Sieckmann, Tobias

AU - Lai, Ethan

AU - Connaughton, Dervla

AU - Seltzsam, Steve

AU - Mann, Nina

AU - Majmundar, Amar

AU - Wu, Chen-Han

AU - Onuchic-Whitford, Ana

AU - Shril, Shirlee

AU - Schneider, Sophia

AU - Schierbaum, Luca

AU - Dai, Rufeng

AU - Bekheirnia, Mir Reza

AU - Joosten, Marieke

AU - Shlomovitz, Omer

AU - Vivante, Asaf

AU - Banne, Ehud

AU - Mane, Shrikant

AU - Lifton, Richard P

AU - Kirschner, Karin

AU - Kispert, Andreas

AU - Rosenberger, Georg

AU - Fischer, Klaus-Dieter

AU - Lienkamp, Soeren

AU - Zegers, Mirjam

AU - Hildebrandt, Friedhelm

PY - 2023/2/1

Y1 - 2023/2/1

N2 - 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.

AB - 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.

U2 - 10.1681/ASN.2022010050

DO - 10.1681/ASN.2022010050

M3 - SCORING: Journal article

C2 - 36414417

VL - 34

SP - 273

EP - 290

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 2

ER -