Human and mouse studies establish TBX6 in Mendelian CAKUT and as a potential driver of kidney defects associated with the 16p11.2 microdeletion syndrome.
Human and mouse studies establish TBX6 in Mendelian CAKUT and as a potential driver of kidney defects associated with the 16p11.2 microdeletion syndrome.
复制标题
人类和小鼠研究证实 TBX6 存在于孟德尔 CAKUT 中，并且是与 16p11.2 微缺失综合征相关的肾脏缺陷的潜在驱动因素
DOI：
10.1016/j.kint.2020.04.045
复制
发表时间：
2020-10
影响因子：
19.6
通讯作者：
Zhang F
中科院分区：
文献类型：
--
作者：
Yang N;Wu N;Dong S;Zhang L;Zhao Y;Chen W;Du R;Song C;Ren X;Liu J;Pehlivan D;Liu Z;Rao J;Wang C;Zhao S;Breman AM;Xue H;Sun H;Shen J;Zhang S;Posey JE;Xu H;Jin L;Zhang J;Liu P;Sanna-Cherchi S;Qiu G;Wu Z;Lupski JR;Zhang F
先天性肾脏和泌尿道异常（CAKUT）是儿童慢性肾脏疾病最常见的原因。人类16p11.2缺失与CAKUT相关，但相关的分子机制仍有待阐明。为了探索这一点，我们调查了来自多中心队列的102名16p11.2缺失携带者，其中我们回顾性地确定了37名个体（12名中国人和25名白人/西班牙人）的肾脏形态和功能数据。在16p11.2缺失携带者中观察到的CAKUT率（中国人约为25%，白人/西班牙人约为16%）显著高于非临床确定的一般人群（尸检发现约为1/1000）。此外，我们还发现了另外7个TBX 6基因（一种定位于16p11.2区域的基因）中具有杂合功能丧失变体的个体。这7例中有4例出现明显CAKUT。为了进一步研究TBX 6在肾脏发育中的作用，我们用突变的Tbx 6等位基因改造小鼠。Tbx 6杂合无效（即，功能丧失）突变体（Tbx 6 +/−）导致13%的孤立肾。值得注意的是，这种发病率增加到29%，在复合杂合模型（Tbx 6 mh/mh），减少Tbx 6基因剂量低于单倍不足，结合无效等位基因与一个新的轻度亚型等位基因（mh）。在这些Tbx 6突变的小鼠模型中也经常观察到肾发育不全。因此，我们在患者和小鼠中的发现将TBX 6确定为参与CAKUT的新基因，并且其基因剂量不足是在16p11.2微缺失综合征中观察到的肾缺陷的潜在驱动因素。
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. Human 16p11.2 deletions have been associated with CAKUT, but the responsible molecular mechanism remains to be illuminated. To explore this, we investigated 102 carriers of 16p11.2 deletion from multi-center cohorts, among which we retrospectively ascertained kidney morphologic and functional data from 37 individuals (12 Chinese and 25 Caucasian/Hispanic). Significantly higher CAKUT rates were observed in 16p11.2 deletion carriers (about 25% in Chinese and 16% in Caucasian/Hispanic) than those found in the non-clinically ascertained general populations (about 1/1000 found at autopsy). Furthermore, we identified seven additional individuals with heterozygous loss-of-function variants in TBX6, a gene that maps to the 16p11.2 region. Four of these seven cases showed obvious CAKUT. To further investigate the role of TBX6 in kidney development, we engineered mice with mutated Tbx6 alleles. The Tbx6 heterozygous null (i.e., loss-of-function) mutant (Tbx6+/−) resulted in 13% solitary kidneys. Remarkably, this incidence increased to 29% in a compound heterozygous model (Tbx6mh/‒) that reduced Tbx6 gene dosage to below haploinsufficiency, by combining the null allele with a novel mild hypomorphic allele (mh). Renal hypoplasia was also frequently observed in these Tbx6-mutated mouse models. Thus, our findings in patients and mice establish TBX6 as a novel gene involved in CAKUT and its gene dosage insufficiency as a potential driver for kidney defects observed in the 16p11.2 microdeletion syndrome.