Mizuno Kentaro, Nakane Akihiro, Nishio Hidenori, Moritoki Yoshinobu, Kamisawa Hideyuki, Kurokawa Satoshi, Kato Taiki, Ando Ryosuke, Maruyama Tetsuji, Yasui Takahiro, Hayashi Yutaro
Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Department of Pediatric urology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan.
BMC Urol. 2017 Dec 2;17(1):112. doi: 10.1186/s12894-017-0300-9.
Congenital anomalies of the kidney and urinary tract (CAKUT), such as renal dysplasia, hydronephrosis, or vesicoureteral reflux, are the most common causes of end-stage renal disease. However, the genetic etiology of CAKUT remains unclear. In this study, we performed whole exome sequencing (WES) to elucidate the genetic etiology of symptomatic CAKUT and CAKUT accompanied by cryptorchidism.
Three patients with unilateral renal dysplasia accompanied by ipsilateral cryptorchidism were included in this analysis. Genomic DNA was extracted from peripheral blood, and WES was performed. Disease-specific single nucleotide polymorphisms (SNPs) were determined by comparison with the human genome reference sequence (hg19). Additionally, we searched for SNPs that were common to all three patients, with a particular focus on the coding regions of the target genes.
In total, 8710 SNPs were detected. Of the genes harboring these SNPs, 32 associated with renal or testicular development were selected for further analyses. Of these, eight genes (i.e., SMAD4, ITGA8, GRIP1, FREM1, FREM2, TNXB, BMP8B, and SALL1) carried a single amino acid substitution that was common to all three patients. In particular, SNPs in SMAD4 (His290Pro and His291Pro) have not been reported previously in patients with symptomatic CAKUT. Of the candidate genes, four genes (i.e., ITGA8, GRIP1, FREM1, and FREM2) were Fraser syndrome-related genes, encoding proteins that functionally converged on the glial cell-derived neurotrophic factor/RET/bone morphogenic protein (BMP) signaling pathways. As another candidate gene, the protein encoded by BMP8B activates the nuclear translocation of SMAD4, which regulates the expression of genes associated with the differentiation of primordial germ cells or testicular development. Additionally, BMP4, a member of the BMP family, regulates the interaction between metanephric mesenchyme and ureteric buds by suppressing GDNF.
Taken together, our findings suggested that the development of the kidney and urinary tract is intimately linked with that of male reproductive organs via BMP/SMAD signaling pathways.
肾脏和尿路先天性异常（CAKUT），如肾发育不全、肾积水或膀胱输尿管反流，是终末期肾病的最常见原因。然而，CAKUT的遗传病因仍不清楚。在本研究中，我们进行了全外显子组测序（WES）以阐明有症状的CAKUT以及伴有隐睾症的CAKUT的遗传病因。
本分析纳入了3例单侧肾发育不全并伴有同侧隐睾症的患者。从外周血中提取基因组DNA，并进行WES。通过与人类基因组参考序列（hg19）比较来确定疾病特异性单核苷酸多态性（SNP）。此外，我们搜索了所有3例患者共有的SNP，特别关注目标基因的编码区。
总共检测到8710个SNP。在含有这些SNP的基因中，选择了32个与肾脏或睾丸发育相关的基因进行进一步分析。其中，8个基因（即SMAD4、ITGA8、GRIP1、FREM1、FREM2、TNXB、BMP8B和SALL1）发生了所有3例患者共有的单个氨基酸替代。特别是，SMAD4中的SNP（His290Pro和His291Pro）在有症状的CAKUT患者中此前尚未有报道。在候选基因中，4个基因（即ITGA8、GRIP1、FREM1和FREM2）是与弗雷泽综合征相关的基因，编码在功能上汇聚于胶质细胞源性神经营养因子/RET/骨形态发生蛋白（BMP）信号通路的蛋白质。作为另一个候选基因，BMP8B编码的蛋白质激活SMAD4的核转位，而SMAD4调节与原始生殖细胞分化或睾丸发育相关的基因的表达。此外，BMP家族成员BMP4通过抑制GDNF来调节后肾间充质与输尿管芽之间的相互作用。
综上所述，我们的研究结果表明，肾脏和尿路的发育通过BMP/SMAD信号通路与男性生殖器官的发育密切相关。
