A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations via Dysregulation 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 () 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.

Kongenitale Anomalien der Nieren und ableitenden Harnwege (CA KUT)

“…Wenn nach dem "knockdown", z. B. von nrip1, ein "rescue" der Pronephrosentwicklung durch eine humane NRIP1-Variante, die mit dem Phänotyp in einer CAKUT-Familie kosegregiert, nicht möglich ist, spricht dies für die Pathogenität der humanen Variante [90]. Auch der Zebrafisch (Danio rerio) eignet sich dafür, die Konsequenz humaner Varianten zu analysieren.…”

Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

“…We previously showed by gene panel sequencing that .10% of CAKUT were monogenic in origin, 42 whereas another 2% of patients were explained by mutations in the Fraser complex of genes. 33 With novel CAKUT gene discovery proceeding at an accelerating rate 43,44 and considering that whole-exome sequencing (WES) is not limited to detection of a prespecified list of candidate genes, we hypothesize that, in .12% of patients with CAKUT, a monogenic cause can be detected by WES.…”

“…33 We and others have evaluated WES data from individuals with CAKUT; however the focus was often on specific subcategories of CAKUT. 36,43,[47][48][49] To date, only one publication has systemically evaluated WES in 62 CAKUT families. 45 We attempted to quantify the prevalence of mutations in known CAKUT genes in a large cohort.…”

Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice

“…22,23 GREB1L has been reported as a target of retinoic acid signaling, a pathway that is crucial for renal development and the dysregulation of which has been proposed as a causative mechanism for urinary tract malformations. 13,[24][25][26] The recent identification of GREB1L mutations in two families with renal agenesis 27 highlighted this gene as a major actor of kidney differentiation. In order to characterize the pattern of GREB1L expression, we first used cDNA panels from various human fetal and adult tissues.…”