Involvement of the bone morphogenic protein/SMAD signaling pathway in the etiology of congenital anomalies of the kidney and urinary tract accompanied by cryptorchidism

BMC Urology

Research Article

Hidenori Nishio¹  Takahiro Yasui¹  Yoshinobu Moritoki¹  Taiki Kato¹  Hideyuki Kamisawa¹  Akihiro Nakane¹  Tetsuji Maruyama¹  Ryosuke Ando¹  Kentaro Mizuno¹  Satoshi Kurokawa¹  Yutaro Hayashi² 

[1] 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;

关键词: Congenital anomalies of the kidney and urinary tract;    Cryptorchidism;    Exome sequencing;    Renal development;   

DOI  :  10.1186/s12894-017-0300-9

 received in 2016-08-25, accepted in 2017-11-16,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundCongenital 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.MethodsThree 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.ResultsIn 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.ConclusionsTaken 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.

【 授权许可】

CC BY   
© The Author(s). 2017