A Gene Implicated in Activation of Retinoic Acid Receptor Targets Is a Novel Renal Agenesis Gene in Humans

Abstract

Renal agenesis (RA) is one of the more extreme examples of congenital anomalies of the kidney and urinary tract (CAKUT). Bilateral renal agenesis is almost invariably fatal at birth, and unilateral renal agenesis can lead to future health issues including end-stage renal disease. Genetic investigations have identified several gene variants that cause RA, including ,, and However, whereas compound null mutations of genes encoding α and γ retinoic acid receptors (RARs) cause RA in mice, to date there have been no reports of variants in RAR genes causing RA in humans. In this study, we carried out whole exome sequence analysis of two families showing inheritance of an RA phenotype, and in both identified a single candidate gene, Analysis of a zebrafish loss-of-function mutant revealed defects in the pronephric kidney just prior to death, and F0 CRISPR/Cas9 mutagenesis of in the mouse revealed kidney agenesis phenotypes, implicating in this disorder. GREB1L resides in a chromatin complex with RAR members, and our data implicate GREB1L as a coactivator for RARs. This study is the first to associate a component of the RAR pathway with renal agenesis in humans.

Targeted gene sequencing and whole‐exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies

“…Family 1 ( Figure 1B, Table 4) and the Iowa family are reported by Brophy et al who presents an argument for the implication of GREB1L in kidney morphogenesis through steroid hormone/retinoic acid receptor target activation. 46 The combination of unilateral kidney agenesis and bilateral kidney agenesis in the same pedigree and the incomplete penetrance of autosomal dominant inherited kidney agenesis have previously been described. 47 We subsequently added GREB1L to our kidney-gene panel and identified another GREB1L variant in 2 fetal siblings with isolated bilateral kidney agenesis.…”

Kongenitale Anomalien der Nieren und ableitenden Harnwege (CA KUT)

“…Dieser starke genetische Effekt mag dadurch begründet sein, dass diese TBX18 "frameshift" Mutation dominant negativ wirkt [89], und Tbx18 die Ureterentwicklung entscheidend reguliert, wie in der Tbx18 "knock-out" Maus gezeigt wurde [3]. Ein weiteres kürzlich beschriebenes CAKUT-Gen, dessen Veränderung zu einem starken genetischen Effekt führt, ist GREB1L [8,14]. In einer Drei-Generationen-Familie war sogar eine heterozygote GREB1L "missense" Mutation mit einem annähernd voll penetranten CAKUT-Phänotyp, einer Nierenagenesie, verbunden [8].…”

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

“…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.…”