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

TitleA Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations Dysregulation of Retinoic Acid Signaling.
Publication TypeJournal Article
Year of Publication2017
AuthorsVivante, A, Mann, N, Yonath, H, Weiss, A-C, Getwan, M, Kaminski, MM, Bohnenpoll, T, Teyssier, C, Chen, J, Shril, S, van der Ven, AT, Ityel, H, Schmidt, JMagdalena, Widmeier, E, Bauer, SB, Sanna-Cherchi, S, Gharavi, AG, Lu, W, Magen, D, Shukrun, R, Lifton, RP, Tasic, V, Stanescu, HC, Cavaillès, V, Kleta, R, Anikster, Y, Dekel, B, Kispert, A, Lienkamp, SS, Hildebrandt, F
JournalJ Am Soc Nephrol
Date Published2017 Aug
KeywordsAdaptor Proteins, Signal Transducing, Animals, Mice, Mutation, Nuclear Proteins, Nuclear Receptor Interacting Protein 1, Signal Transduction, Tretinoin, Urinary Tract

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

Alternate JournalJ. Am. Soc. Nephrol.
PubMed ID28381549
PubMed Central IDPMC5533226
Grant ListR01 DK088767 / DK / NIDDK NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
S10 OD018521 / OD / NIH HHS / United States
R01 DK078226 / DK / NIDDK NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
T32 DK007726 / DK / NIDDK NIH HHS / United States