A Gene Implicated in Activation of Retinoic Acid Receptor Targets Is a Novel Renal Agenesis Gene in Humans
A Gene Implicated in Activation of Retinoic Acid Receptor Targets Is a Novel Renal Agenesis Gene in Humans
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DOI：
10.1534/genetics.117.1125
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发表时间：
2017-09-01
期刊：
影响因子：
3.3
通讯作者：
Manak, J. Robert
中科院分区：
文献类型：
--
作者：
Brophy, Patrick D.;Rasmussen, Maria;Manak, J. Robert
肾发育不全（RA）是先天性肾脏和泌尿道异常（CAKUT）的一个更极端的例子。双侧肾发育不全在出生时几乎总是致命的，单侧肾发育不全可能导致未来的健康问题，包括终末期肾病。遗传学研究已经确定了导致RA的几种基因变体，包括EYA 1，LHX 1和WT 1。然而，尽管编码α和γ维甲酸受体（RAR）的基因的复合无效突变导致小鼠中的RA，但迄今为止还没有RAR基因的变体导致人类中的RA的报道。在这项研究中，我们进行了整个外显子序列分析的两个家庭显示遗传的RA表型，并在两个确定了一个单一的候选基因，GREB 1 L。对斑马鱼greb 1 l功能丧失突变体的分析显示，死亡前肾有缺陷，而小鼠中Greb 1 l的F0 CRISPR/Cas9诱变显示了肾脏发育不全的表型，表明Greb 1 l与这种疾病有关。GREB 1 L存在于与RAR成员的染色质复合物中，我们的数据暗示GREB 1 L是RAR的共激活剂。这项研究是第一个将RAR通路的一个组成部分与人类肾脏发育不全相关联的研究。
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 EYA1, LHX1, and WT1. However, whereas compound null mutations of genes encoding alpha and gamma 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, GREB1L. Analysis of a zebrafish greb1l loss-of-function mutant revealed defects in the pronephric kidney just prior to death, and F0 CRISPR/Cas9 mutagenesis of Greb1l in the mouse revealed kidney agenesis phenotypes, implicating Greb1l 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.