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

TY - JOUR

T1 - A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations via Dysregulation of Retinoic Acid Signaling

AU - Vivante, Asaf

AU - Mann, Nina

AU - Yonath, Hagith

AU - Weiss, Anna-Carina

AU - Getwan, Maike

AU - Kaminski, Michael M

AU - Bohnenpoll, Tobias

AU - Teyssier, Catherine

AU - Chen, Jing

AU - Shril, Shirlee

AU - van der Ven, Amelie T

AU - Ityel, Hadas

AU - Schmidt, Johanna Magdalena

AU - Widmeier, Eugen

AU - Bauer, Stuart B

AU - Sanna-Cherchi, Simone

AU - Gharavi, Ali G

AU - Lu, Weining

AU - Magen, Daniella

AU - Shukrun, Rachel

AU - Lifton, Richard P

AU - Tasic, Velibor

AU - Stanescu, Horia C

AU - Cavaillès, Vincent

AU - Kleta, Robert

AU - Anikster, Yair

AU - Dekel, Benjamin

AU - Kispert, Andreas

AU - Lienkamp, Soeren S

AU - Hildebrandt, Friedhelm

N1 - Copyright © 2017 by the American Society of Nephrology.

PY - 2017/8

Y1 - 2017/8

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing/genetics

KW - Animals

KW - Mice

KW - Mutation

KW - Nuclear Proteins/genetics

KW - Nuclear Receptor Interacting Protein 1

KW - Signal Transduction/genetics

KW - Tretinoin/physiology

KW - Urinary Tract/abnormalities

U2 - 10.1681/ASN.2016060694

DO - 10.1681/ASN.2016060694

M3 - SCORING: Journal article

C2 - 28381549

VL - 28

SP - 2364

EP - 2376

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 8

ER -