title: A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract MalformationsviaDysregulation of Retinoic Acid Signaling.
abstract: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of CKD in the first three decades of life. However, for most patients with CAKUT, the causative mutation remains unknown. We identified a kindred with an autosomal dominant form of CAKUT. By whole-exome sequencing, we identified a heterozygous truncating mutation (c.279delG, p.Trp93fs*) of the nuclear receptor interacting protein 1 gene (NRIP1) in all seven affected members.NRIP1encodes a nuclear receptor transcriptional cofactor that directly interacts with the retinoic acid receptors (RARs) to modulate retinoic acid transcriptional activity. Unlike wild-type NRIP1, the altered NRIP1 protein did not translocate to the nucleus, did not interact with RARα, and failed to inhibit retinoic acid-dependent transcriptional activity upon expression in HEK293 cells. Notably, we also showed that treatment with retinoic acid enhanced NRIP1 binding to RARαRNAin situhybridization confirmedNrip1expression in the developing urogenital system of the mouse. In explant cultures of embryonic kidney rudiments, retinoic acid stimulatedNrip1expression, whereas a pan-RAR antagonist strongly reduced it. Furthermore, mice heterozygous for a null allele ofNrip1showed a CAKUT-spectrum phenotype. Finally, expression and knockdown experiments inXenopus laevisconfirmed an evolutionarily conserved role forNRIP1in renal development. These data indicate that dominantNRIP1mutations can cause CAKUT by interference with retinoic acid transcriptional signaling, shedding light on the well documented association between abnormal vitamin A levels and renal malformations in humans, and suggest a possible gene-environment pathomechanism in this disease.
authors.affiliation: Departments of Medicine and.|Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Vivante
authors.affiliation: Departments of Medicine and.
authors.forename: Nina
authors.initials: N
authors.lastname: Mann
authors.affiliation: Department of Internal Medicine A and Genetics Institute, Sheba Medical Center and Sackler Faculty of Medicine Tel Aviv University, Tel Aviv, Israel.
authors.forename: Hagith
authors.initials: H
authors.lastname: Yonath
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Anna-Carina
authors.initials: AC
authors.lastname: Weiss
authors.affiliation: Department of Medicine, Renal Division, University Medical Center, Faculty of Medicine, and.
authors.forename: Maike
authors.initials: M
authors.lastname: Getwan
authors.affiliation: Department of Medicine, Renal Division, University Medical Center, Faculty of Medicine, and.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Kaminski
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bohnenpoll
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier (IRCM), Montpellier, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Montpellier, France; Université Montpellier, Montpellier, France; Institut régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Teyssier
authors.affiliation: Departments of Medicine and.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Departments of Medicine and.
authors.forename: Shirlee
authors.initials: S
authors.lastname: Shril
authors.affiliation: Departments of Medicine and.
authors.forename: Amelie T
authors.initials: AT
authors.lastname: van der Ven
authors.affiliation: Departments of Medicine and.
authors.forename: Hadas
authors.initials: H
authors.lastname: Ityel
authors.affiliation: Departments of Medicine and.
authors.forename: Johanna Magdalena
authors.initials: JM
authors.lastname: Schmidt
authors.affiliation: Departments of Medicine and.|Department of Medicine, Renal Division, University Medical Center, Faculty of Medicine, and.
authors.forename: Eugen
authors.initials: E
authors.lastname: Widmeier
authors.affiliation: Urology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Bauer
authors.affiliation: Division of Nephrology, Columbia University, New York, New York.
authors.forename: Simone
authors.initials: S
authors.lastname: Sanna-Cherchi
authors.affiliation: Division of Nephrology, Columbia University, New York, New York.
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
authors.affiliation: Renal Section, Department of Medicine, Boston University Medical Center, Boston, Massachusetts.
authors.forename: Weining
authors.initials: W
authors.lastname: Lu
authors.affiliation: Pediatric Nephrology Institute, Rambam Health Care Campus, and Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Daniella
authors.initials: D
authors.lastname: Magen
authors.affiliation: Department of Pediatrics, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Shukrun
authors.affiliation: Department of Human Genetics, Yale University School of Medicine, New Haven, Connecticut.|Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Department of Pediatric Nephrology, Medical Faculty Skopje, University Children's Hospital, Skopje, Macedonia; and.
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.affiliation: Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Horia C
authors.initials: HC
authors.lastname: Stanescu
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier (IRCM), Montpellier, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Montpellier, France; Université Montpellier, Montpellier, France; Institut régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cavaillès
authors.affiliation: Centre for Nephrology, University College London, London, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Department of Pediatrics, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.affiliation: Department of Pediatrics, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dekel
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.affiliation: Department of Medicine, Renal Division, University Medical Center, Faculty of Medicine, and.|Center for Biological Signaling Studies (BIOSS), Albert Ludwig University, Freiburg, Germany.
authors.forename: Soeren S
authors.initials: SS
authors.lastname: Lienkamp
authors.affiliation: Departments of Medicine and Friedhelm.Hildebrandt@childrens.harvard.edu.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000078723:Nuclear Receptor Interacting Protein 1; D015398:Signal Transduction / Q000235:genetics*; D014212:Tretinoin / Q000502:physiology*; D014551:Urinary Tract / Q000002:abnormalities*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000627127:NRIP1 protein, human; C000627128:Nrip1 protein, mouse; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D014212:Tretinoin
keywords: CAKUT; NRIP1; retinoic acid