Vivante, A; Mann, N; Yonath, H; Weiss, A-C; Getwan, M; Kaminski, MM; Bohnenpoll, T; ... Hildebrandt, F; + view all Vivante, 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, JM; 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; - view fewer (2017) A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations via Dysregulation of Retinoic Acid Signaling. Journal of the American Society of Nephrology , 28 (8) pp. 2364-2376. 10.1681/ASN.2016060694.

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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.

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