A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations via Dysregulation of Retinoic Acid Signaling

J Am Soc Nephrol. 2017 Aug;28(8):2364-2376. doi: 10.1681/ASN.2016060694.

Asaf Vivante ¹ ², Nina Mann ¹, Hagith Yonath ³, Anna-Carina Weiss ⁴, Maike Getwan ⁵, Michael M Kaminski ⁵, Tobias Bohnenpoll ⁴, Catherine Teyssier ⁶, Jing Chen ¹, Shirlee Shril ¹, Amelie T van der Ven ¹, Hadas Ityel ¹, Johanna Magdalena Schmidt ¹, Eugen Widmeier ¹ ⁵, Stuart B Bauer ⁷, Simone Sanna-Cherchi ⁸, Ali G Gharavi ⁸, Weining Lu ⁹, Daniella Magen ¹⁰, Rachel Shukrun ¹¹, Richard P Lifton ¹² ¹³, Velibor Tasic ¹⁴, Horia C Stanescu ¹⁵, Vincent Cavaillès ⁶, Robert Kleta ¹⁵, Yair Anikster ¹¹, Benjamin Dekel ¹¹, Andreas Kispert ⁴, Soeren S Lienkamp ⁵ ¹⁶, Friedhelm Hildebrandt ¹⁷

Affiliations

1 Departments of Medicine and.
2 Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.
3 Department of Internal Medicine A and Genetics Institute, Sheba Medical Center and Sackler Faculty of Medicine Tel Aviv University, Tel Aviv, Israel.
4 Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany.
5 Department of Medicine, Renal Division, University Medical Center, Faculty of Medicine, and.
6 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.
7 Urology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
8 Division of Nephrology, Columbia University, New York, New York.
9 Renal Section, Department of Medicine, Boston University Medical Center, Boston, Massachusetts.
10 Pediatric Nephrology Institute, Rambam Health Care Campus, and Technion-Israel Institute of Technology, Haifa, Israel.
11 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.
12 Department of Human Genetics, Yale University School of Medicine, New Haven, Connecticut.
13 Howard Hughes Medical Institute, Chevy Chase, Maryland.
14 Department of Pediatric Nephrology, Medical Faculty Skopje, University Children's Hospital, Skopje, Macedonia; and.
15 Centre for Nephrology, University College London, London, United Kingdom.
16 Center for Biological Signaling Studies (BIOSS), Albert Ludwig University, Freiburg, Germany.
17 Departments of Medicine and Friedhelm.Hildebrandt@childrens.harvard.edu.

PMID: 28381549 DOI: 10.1681/ASN.2016060694

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. NRIP1 encodes 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 RARα RNA in situ hybridization confirmed Nrip1 expression in the developing urogenital system of the mouse. In explant cultures of embryonic kidney rudiments, retinoic acid stimulated Nrip1 expression, whereas a pan-RAR antagonist strongly reduced it. Furthermore, mice heterozygous for a null allele of Nrip1 showed a CAKUT-spectrum phenotype. Finally, expression and knockdown experiments in Xenopus laevis confirmed an evolutionarily conserved role for NRIP1 in renal development. These data indicate that dominant NRIP1 mutations 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.

Keywords

CAKUT; NRIP1; retinoic acid.

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