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

  • 1,
  • 1,
  • 1,
  • 1,
  • 1,
  • 1,
  • 1,
  • 1,
  • 1,
  • 1 and
  • 2Email author
BMC UrologyBMC series – open, inclusive and trusted201717:112

  • Received: 25 August 2016
  • Accepted: 16 November 2017
  • Published:
Open Peer Review reports



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.


  • Congenital anomalies of the kidney and urinary tract
  • Cryptorchidism
  • Exome sequencing
  • Renal development


Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately 40–50% cases of end-stage renal disease in children [1]. CAKUT is a comprehensive disease concept, including renal hypoplasia, dysplasia, hydronephrosis (ureteropelvic junction obstruction or ureterovesical junction obstruction), ureter duplex, vesicoureteral reflux, and posterior urethral valves [2]. The incidence of CAKUT is estimated to be 3–6 per 1000 live births [3]. In general, the structural anomalies found in patients with CAKUT are often related because impaired codevelopment of nephrogenic tissues derived from the metanephric mesenchyme and ureteric bud is thought to contribute to the pathogenesis of CAKUT [4]. Thus, the etiology of CAKUT is heterogeneous and includes mutations in genes involved in the embryonic development of the kidneys [2]. A previous study showed that monogenic causes could be detected in about 12% of patients [5]. Thus, elucidating the genetic etiology of CAKUT is important for the diagnosis of asymptomatic renal disease, advanced diagnosis of inheritance patterns, and referral to genetic counseling in the clinical setting [2].

While CAKUT most frequently occurs as an isolated case and without renal or urinary tract structural anomalies or symptoms, it may also appear with other systemic disorders, such as Fraser syndrome [1], Hirchsprung disease [6], or vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities (VACTERL association) [7]. Notably, anomalies in the epididymis are sometimes encountered during surgery for cryptorchidism. Although the complete mechanism of testicular descent remains unclear, a recent study revealed that maldevelopment of the epididymis is associated with problems in testicular descent [8]. Because both the epididymis and ureteric bud are embryologically derived from the mesonephric duct, we hypothesized that a common mechanism may be responsible for the maldevelopment of the ureteric bud and impaired testicular descent. A previous study demonstrated that the pathogenesis of CAKUT is associated with mutations in several genes, including HNF1B, PAX2, or SALL1 [9]. In contrast, studies in knockout mice [10, 11] and genome-wide association studies [12] have shown that INSL3 and TGFBR3 are involved in the onset of cryptorchidism. However, few reports have described the genetic etiology of CAKUT accompanied by cryptorchidism [13].

Thus, in the present study, whole-exome sequencing (WES) was used to elucidate the genetic etiology of “symptomatic CAKUT,” i.e., CAKUT accompanied by cryptorchidism. We identified single nucleotide polymorphisms (SNPs) common to all patients and detected 10 non-synonymous SNPs from eight genes known to be associated with CAKUT or testicular development, including BMP8B and SMAD4, whose gene products function in the same signaling pathway. Our findings provide important insights into the relationship between renal and testicular development and these signaling pathways.


Patients and sample preparation

From patients who were treated or followed-up at Nagoya City University Hospital from July 2011 to January 2015, three patients with CAKUT complicated by ipsilateral cryptorchidism were enrolled in this study. Patient characteristics are shown in Table 1. At the initial visit, every patient was referred to our hospital because scrotal contents were absent and abdominal ultrasonography, computed tomography (CT) scanning, or magnetic resonance imaging (MRI) examinations revealed renal aplasia or multicystic dysplastic kidney. Case 3 had a pelvic dysplastic kidney and underwent ipsilateral nephrectomy simultaneously with orchiectomy for abdominal testis. Chromosome analysis was performed for all patients; case 3 showed chromosomal abnormality (46,Y, add (X) (p22.3)). Genomic DNA was extracted from the peripheral blood of the patients using a Wizard genomic DNA purification kit, according to the manufacturer’s instructions, as previously reported [14]. The purity of the extracted DNA was determined by measuring the absorbance and visually by gel electrophoresis.
Table 1

Patient characteristics

Case No.






Right renal aplasia, Right abdominal testis, Agenesis of right vas deferens and seminal vesicle

31 y


Laparoscopic right orchiopexy


Left multicystic dysplastic kidney, Bil. cryptorchidism, Micropenis

1 y


Laparoscopic bilateral orchiopexy


Left multicystic dysplastic kidney (pelvis), Left abdominal testis, Agenesis of left vas deferens

2 y

46,Y, add(X) (p22.3)


left nephrectomy

left orchiectomy

WES analysis

Whole exons were purified from genomic DNA using a SureSelevtXT Human All Exon v5 Kit (Agilent Technologies, Santa Clara, CA, USA). After ligation of specific adaptors for exon fragments, paired-end sequencing was performed on a Hiseq 2500 instrument (Illumina Inc., San Diego, CA, USA). Raw sequence data in fastq format were uploaded to the DNAnexus platform server (DNAnexus Inc., San Francisco, CA, USA) and aligned to the human reference genome (hg19). After all data were exported to Microsoft Excel and Access, we searched for SNPs that were common to all three patients, with a particular focus on the coding region.

SNP analysis at specific gene loci

Next, we selected 32 genes that have been reported to be associated with CAKUT or testicular development: BMP7, CDC5L, CHD1L, GATA3, HNF1B, PAX2, RET, ROBO2, SALL1, SIX2, SIX5, EYA2 [9], FRAS1, FREM2, GRIP1, FREM1, ITGA8, GREM1, ILK, LIN7C, DACT1 [1], TNXB [15], DSTYK [16], WNT4, WT1, PAX7 [17], SALL4 [18, 19], BMP4, SMAD4 [20], BMP8B [21], GDNF, and GFRA1 [13]. From the WES data, we evaluated SNPs in these 32 genes. We further examined the shared SNPs among 3 cases using by subsequent filtering of variants based on their frequencies (minor allele frequency (MAF)) in databases including Exome Aggregation Consortium (ExAC), 1000 Genome Project, Exome Variant Server (ESP).

Ethics statement

Studies using human genomic material were performed only after obtaining written informed consent from the patient (case 1) and the families of the patients and approval from the Nagoya City University Hospital review board (approval no. 184).


The total number of sequencing reads for all exons of the three patients (cases 1, 2, and 3) were 55,657,960, 50,214,710, and 55,301,946, respectively. To improve the accuracy of the SNP data, raw data were filtered using the DNAnexus platform server under the following conditions: variant score > 30, iRef >30, and coverage >30. Subsequently, the numbers of SNPs in cases 1, 2, and 3 were decreased to 84,810, 76,182, and 82,791, respectively. In total, 8710 SNPs were common to all three patients (Fig. 1). The chromosomal locations of these SNPs were determined; chromosomes 1, 11, 12, 17, and 19 showed the highest number of SNPs. Chromosome Y harbored only two SNPs (Fig. 2).
Fig. 1
Fig. 1

Filtering scheme for identification of common SNPs in three patients with CAKUT accompanied by cryptorchidism. The number of SNPs in each patient was decreased at each step

Fig. 2
Fig. 2

Graphical view of the number of SNPs in each chromosome. The number of SNPs was greater in chromosomes 1, 11, 12, 17, and 19 than in the other chromosomes. Chromosome Y had only two SNPs

We further investigated the SNPs within 32 specific gene loci and detected 10 non-synonymous SNPs within eight genes (Table 2). Of these SNPs, two in SMAD4 had not been reported previously, suggesting that these may be novel variants in patients with CAKUT. SMAD4 is a central mediator of the transforming growth factor (TGF)-β/bone morphogenic protein (BMP) signaling pathway and promotes transcriptional activation of target genes [22]. We also detected an SNP in BMP8B (rs179472; Ser276Thr). BMP8B belongs to the TGF-β superfamily and triggers the phosphorylation of intracellular receptor-regulated SMADs (R-SMADs), which function as transcription factors. Phosphorylated R-SMAD interacts with SMAD4 and translocates to the nucleus, where it regulates the transcription of over 500 target genes [23]. SNPs in ITGA8, GRIP1, FREM1, and FREM2 have been reported in a WES study of patients with isolated CAKUT [1]; however, these findings were not consistent with our results. In addition, although a deleterious heterozygous mutation in TNXB (Thr3257Ile) has been shown to cause hereditary vesicoureteral reflux (VUR) [15], this was not true for the SNP detected in the present study (rs6457477; Arg504His). Moreover, the SNP identified in SALL1 (rs4614723; Val1178Ile) was different from that reported in a WES study for familial CAKUT [9]; however, the same SNP was reported in a previous case report [24]. MAF of SNPs in SMAD4 and FREM2 (rs2496423) is lower than 1%, and remaining 7 SNPs in 7 genes are more common in the general population.
Table 2

Genes and SNPs common to patients with CAKUT accompanied by cryptorchidism

Gene Symbol

Gene Name

Gene ID

Chromosomal location




Amino acid replacement


SMAD family member 4


chr18: 48584791





chr18: 48584794





Integrin a8


chr10: 15573050






Glutamate receptor interacting protein 1


chr12: 66786091






FRAS1 related extracellular matrix protein 2


chr13: 39263714






chr13: 39,430,314






FRAS1 related extracellular matrix protein 1


chr9: 14737506






Tenascin XB


chr6: 31977391






Bone morphogenetic protein 8b


chr1: 40230336






Spalt-like transcription factor 1


chr16: 51171175






In the present study, we performed WES of samples from three patients with CAKUT accompanied by cryptorchidism to elucidate the genetic etiology of the disease. We detected 10 non-synonymous SNPs in the coding regions of eight genes. In particular, we identified two novel SNPs in SMAD4 (His290Pro and His291Pro) and one SNP in BMP8B (rs179472; Ser276Thr). Both BMP8B and SMAD4 function in the same signaling pathway, and it is likely that this pathway is involved in the etiology in CAKUT accompanied by cryptorchidism. The other candidate SNPs (ITGA8, GRIP1, FREM1, FREM2, TNXB, and SALL1) identified in this study were consistent with previous WES studies examining isolated or familial CAKUT [1, 9, 15, 24]. In particular, four of these genes (i.e., ITGA8, GRIP1, FREM1, and FREM2) were Fraser syndrome-related genes reported previously by Kohl et al. [1]. Fraser syndrome is a rare autosomal-recessive disorder with features of cryptophthalmos, syndactyly, ambiguous genitalia, laryngeal and genitourinary malformations, oral clefting, and mental retardation [25]. Because such mutated Fraser syndrome-related genes encode proteins that functionally converge on the glial cell-derived neutotrophic factor (GDNF)-RET/BMP signaling pathways at the interface of the ureteric bud and metanephric mesenchyme [1], these results also supported our hypothesis that alterations in the BMP/SMAD signaling pathway may cause renal maldevelopment with ipsilateral cryptorchidism. In case 3 patient, he has chromosomal abnormality (46,Y, add(X)(p22.3)). This chromosomal abnormality means addition of unknown fragment to terminal end of the short arm of X chromosome. Although there is the possibility that this chromosomal abnormality provide cause of his phenotype, there are no common SNPs in X chromosome among 3 cases.

In humans, the metanephros is the structure that develops into the kidneys. This structure begins to form as the ureteric bud at about 4 weeks of gestation [26]. The ureteric bud invades the metanephric mesenchyme and undergoes recursive branching to form the collecting system of the urinary tract [13]. The key regulators of primary ureteric bud outgrowth and branching are GDNF, which is secreted by the metanephric mesenchyme, and its receptor RET, which is expressed on the ureteric bud [27]. Following the binding of RET, a receptor tyrosine kinase, to the GDNF coreceptor GDNF family receptor α-1 (GFRA1), GDNF activates the RET/GFRA1 receptor tyrosine kinase and thereby triggers a signaling cascade that includes the extracellular signal-regulated kinase (ERK), phosphoinositol 3-kinase (PI3K), and phospholipase (PLC) ζ pathways [13]. Activation of these pathways eventually leads to the outgrowth of the ureteric bud and subsequent renal development [27]. As an upstream regulator of the GDNF-RET/GFRA1 signaling pathway, BMP4 acts as a negative regulator [28]. Moreover, as members of the TGF-β superfamily, BMPs regulate gene expression by receptor-mediated activation of SMAD transcription factors [23]. Therefore, the BMP/SMAD and GDNF-RET/GFRA1 signaling pathways are intimately involved in the development of the ureteric bud, which is derived from the metanephric duct, during the early phase of renal development.

Several studies have reported the role of the BMP/SMAD signaling pathway in testicular development. BMP4 and BMP8B are important for the specification of primordial germ cells during fetal development [29], and SMAD4 and SMAD3 are necessary for the proliferation and maturation of fetal Sertoli cells [29]. The GDNF-RET/GFRA1 signaling pathway is also associated with spermatogenesis, and GDNF is essential for the self-renewal and differentiation of spermatogonial stem cells [30]. Cryptorchidism is a multifactorial disease, and its etiology is linked to multiple genomic loci as well as maternal and/or environmental factors. The genomic loci and pathways involved in its etiology remain unclear; however, Barthold et al. recently reported a phenotype-specific association of the TGFBR3 locus with nonsyndromic cryptorchidism [12]. Furthermore, SMAD4 mutations have been identified in patients with Myhre syndrome, which features cryptorchidism [31].

In the present study, non-synonymous SNPs in both BMP8B and SMAD4 loci were found to be common to all patients with CAKUT accompanied by cryptorchidism, suggesting that impairment of the BMP/SMAD signaling pathway was likely involved in the pathogenesis of this condition. Furthermore, because renal anomalies and cryptorchidism were ipsilateral in all our patients, it is likely that development of the ipsilateral metanephric duct was impaired in these patients. CAKUT is a comprehensive disease concept that encompasses a wide array of phenotypes. To elucidate the genetic etiology of CAKUT, it will be necessary to analyze a greater number of cases. Indeed, several studies on isolated or familial CAKUT have been planned and reported [1, 2, 5, 9, 13]; however, narrowing down the patient setting can reduce the number of cases that need to be studied in order to determine the associated gene loci.

To date, several WES studies have been reported, with the aim of elucidating the genetic cause of CAKUT [5, 3234]. Consequently, mutations in the ZBTB24, WFS1, HPSE2, ATRX, ASPH, AGXT, AQP2, CTNS, PKHD1 [5], TBX18 [32], SLIT2, SRGAP1 [33], and TBC1D1 genes [34] have been identified. Although these results did not include our candidate SNPs, we assumed that this discrepancy was related to our focus on cases of CAKUT accompanied by cryptorchidism. Genome-wide analyses have made it possible to investigate multiple gene loci simultaneously. Chatterjee et al. investigated mutations in several genes involved in the GDNF-RET signaling pathway and subsequently detected double non-synonymous variants of RET (G691S/R982C) in a patient with complex CAKUT and cryptorchidism [13]. They also reported that the CAKUT and cryptorchidism phenotypes could be explained by the occurrence of a combination of rare, novel, and common deleterious variants affecting the RET pathway. However, the complete pathological mechanism can only be explained by genome-wide analyses because monogenic causes are detected in only 5–12% of patients [5, 13]. Exons account for only 2% of the whole genome, and the roles of noncoding regions or epigenetics in CAKUT remain unclear. Indeed, we have previously demonstrated that copy number variations in the region upstream of SOX3, suspected to act as a promoter or enhancer, are associated with testicular differentiation [14].

The present study had several limitations. First, the sample size used in the study was too small to investigate a specific phenotype. Moreover, we did not determine whether genetic variations in these eight genes resulted in a dysfunction at the protein level. We investigated the effects of the identified amino acid substitutions on protein function using the SIFT platform ( All 10 SNPs detected in the present study were predicted to be tolerant in the in silico analysis (data not shown). Besides, MAF of SNPs in SMAD4 and FREM2 (rs2496423) is lower than 1%, suggesting that these rare variants is possibly pathogenic for CAKUT accompanied with by cryptorchidism. Further investigations are needed to determine whether other factors associated with the BMP/SMAD signaling pathway are involved in the onset of CAKUT with cryptorchidism.


We detected 10 non-synonymous SNPs in eight genes in patients with CAKUT accompanied by cryptorchidism. These SNPs were candidate polymorphisms associated with the development of the kidney, urinary tract, and testis. BMP8B is known to activate 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 the metanephric mesenchyme and ureteric bud by suppressing GDNF. Taken together, these findings suggested that the developmental mechanisms of the kidneys and urinary tract were intimately linked with that of the male reproductive organs through genetic alterations.



Congenital anomalies of kidney and urinary tract


Single nucleotide polymorphism


Whole exome sequencing



The authors are grateful to the laboratory technician, Ms. Kasuga, Ms. Noda, and Ms. Ando who provided preservation and preparation of samples. And the 261st JUA Tokai Divisional Meeting Best Presentation Award was given for the case of this manuscript.


This work was supported by JSPS KAKENHI Grant Number 26462421.

Availability of data and materials

The datasets generated during and/or analysed during the current study are not publicly available due to restrictions of our Institutional Review Board but are available from the corresponding author on reasonable request.

Authors’ contributions

Conception and design: KM, AN, and YH; enrollment of patients and acquisition of data: KM, HN, and TK; drafting of the manuscript: KM and YH; data mining of whole exome sequencing and statistical analysis: KM, YM, HK, SK, and TM; analysis and interpretation of data: RA and TY; supervision: YH. We confirm that all authors read and approved the final manuscript.

Ethics approval and consent to participate

Studies using human genomic material were performed only after obtaining written informed consent from the patients or families of the patients and Nagoya City University Hospital institutional review board approval (No.184).

Consent for publication

Written informed consent was obtained from the patient and their parents for publication of this report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

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


  1. Kohl S, Hwang DY, Dworschak GC, Hilger AC, Saisawat P, Vivante A, et al. Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol. 2014;25:1917–22.View ArticlePubMedPubMed CentralGoogle Scholar
  2. Vivante A, Kohl S, Hwang DY, Dworschak GC, Hildebrandt F. Single-gene causes of congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Pediatr Nephrol. 2014;29:695–704.View ArticlePubMedPubMed CentralGoogle Scholar
  3. Harambat J, van Stralen KJ, Kim JJ, Tizard EJ. Epidemiology of chronic kidney disease in children. Pediatr Nephrol. 2012;27:363–73.View ArticlePubMedGoogle Scholar
  4. Ichikawa I, Kuwayama F, Pope JC 4th, Stephens FD, Miyazaki Y. Paradigm shift from classic anatomic theories to contemporary cell biological views of CAKUT. Kidney Int. 2002;61:889–98.View ArticlePubMedGoogle Scholar
  5. Vivante A, Hwang DY, Kohl S, Chen J, Shril S, Schulz J, et al. Exome sequencing discerns syndromes in patients from consanguineous families with congenital anomalies of the kidneys and urinary tract. J Am Soc Nephrol. 2017;28:69–75.View ArticlePubMedGoogle Scholar
  6. Pini Prato A, Musso M, Ceccherini I, Mattioli G, Giunta C, Ghiggeri GM, et al. Hirschsprung disease and congenital anomalies of the kidney and urinary tract (CAKUT): a novel syndromic association. Medicine (Baltimore). 2009;88:83–90.View ArticleGoogle Scholar
  7. Saisawat P, Kohl S, Hilger AC, Hwang DY, Yung Gee H, Dworschak GC, et al. Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. Kidney Int. 2014;85:1310–7.View ArticlePubMedGoogle Scholar
  8. Hadziselimovic F. Involvement of fibroblast growth factors and their receptors in epididymo-testicular descent and maldescent. Mol Syndromol. 2016;6:261–7.View ArticlePubMedPubMed CentralGoogle Scholar
  9. Hwang DY, Dworschak GC, Kohl S, Saisawat P, Vivante A, Hilger AC, et al. Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. Kidney Int. 2014;85:1429–33.View ArticlePubMedPubMed CentralGoogle Scholar
  10. Nef S, Parada LF. Cryptorchidism in mice mutant for Insl3. Nat Genet. 1999;22:295–9.View ArticlePubMedGoogle Scholar
  11. Zimmermann S, Steding G, Emmen JM, Brinkmann AO, Nayernia K, Holstein AF, et al. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol. 1999;13:681–91.View ArticlePubMedGoogle Scholar
  12. Barthold JS, Wang Y, Kolon TF, Kollin C, Nordenskjöld A, Olivant Fisher A, et al. Phenotype-specific association of the TGFBR3 locus with nonsyndromic cryptorchidism. J Urol. 2015;193:1637–45.View ArticlePubMedGoogle Scholar
  13. Chatterjee R, Ramos E, Hoffman M, VanWinkle J, Martin DR, Davis TK, et al. Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations. Hum Genet. 2012;131:1725–38.View ArticlePubMedPubMed CentralGoogle Scholar
  14. Mizuno K, Kojima Y, Kamisawa H, Moritoki Y, Nishio H, Nakane A, et al. Elucidation of distinctive genomic DNA structures in patients with 46,XX testicular disorders of sex development using genome-wide analyses. J Urol. 2014;192:535–41.View ArticlePubMedGoogle Scholar
  15. Gbadegesin RA, Brophy PD, Adeyemo A, Hall G, Gupta IR, Hains D, et al. TNXB mutations can cause vesicoureteral reflux. J Am Soc Nephrol. 2013;24:1313–22.View ArticlePubMedPubMed CentralGoogle Scholar
  16. Sanna-Cherchi S, Sampogna RV, Papeta N, Burgess KE, Nees SN, Perry BJ, et al. Mutations in DSTYK and dominant urinary tract malformations. N Engl J Med. 2012;369:621–9.View ArticleGoogle Scholar
  17. Aloisio GM, Nakada Y, Saatcioglu HD, Peña CG, Baker MD, Tarnawa ED, et al. PAX7 expression defines germline stem cells in the adult testis. J Clin Invest. 2014;124:3929–44.View ArticlePubMedPubMed CentralGoogle Scholar
  18. Yamaguchi YL, Tanaka SS, Kumagai M, Fujimoto Y, Terabayashi T, Matsui Y, et al. Sall4 is essential for mouse primordial germ cell specification by suppressing somatic cell program genes. Stem Cells. 2015;33:289–300.View ArticlePubMedGoogle Scholar
  19. Toyoda D, Taguchi A, Chiga M, Ohmori T, Nishinakamura R. Sall4 is transiently expressed in the caudal Wolffian duct and the ureteric bud, but dispensable for kidney development. PLoS One. 2013;8:e68508.View ArticlePubMedPubMed CentralGoogle Scholar
  20. Tripathi P, Wang Y, Casey AM, Chen F. Absence of canonical Smad signaling in ureteral and bladder mesenchyme causes ureteropelvic junction obstruction. J Am Soc Nephrol. 2012;23:618–28.View ArticlePubMedPubMed CentralGoogle Scholar
  21. Ciller IM, Palanisamy SK, Ciller UA, McFarlane JR. Postnatal expression of bone morphogenetic proteins and their receptors in the mouse testis. Physiol Res. 2016; [Epub ahead of print]Google Scholar
  22. Yan J, Zhang L, Xu J, Sultana N, Hu J, Cai X, et al. Smad4 regulates ureteral smooth muscle cell differentiation during mouse embryogenesis. PLoS One. 2014;9:e104503.View ArticlePubMedPubMed CentralGoogle Scholar
  23. Massagué J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012;13:616–30.View ArticlePubMedPubMed CentralGoogle Scholar
  24. Liang Y, Shen D, Cai W. Two coding single nucleotide polymorphisms in the SALL1 gene in Townes-brocks syndrome: a case report and review of the literature. J Pediatr Surg. 2008;43:391–3.View ArticlePubMedGoogle Scholar
  25. Slavotinek A, Li C, Sherr EH, Chudley AE. Mutation analysis of the FRAS1 gene demonstrates new mutations in a propositus with Fraser syndrome. Am J Med Genet A. 2006;140:1909–14.View ArticlePubMedGoogle Scholar
  26. Dressler GR. The cellular basis of kidney development. Annu Rev Cell Dev Biol. 2006;22:509–29.View ArticlePubMedGoogle Scholar
  27. Krause M, Rak-Raszewska A, Pietila I, Quaggin SE, Vainio S. Signaling during kidney development. Cell. 2015;4:112–32.View ArticleGoogle Scholar
  28. Davis TK, Hoshi M, Jain S. To bud or not to bud: the RET perspective in CAKUT. Pediatr Nephrol. 2014;29:597–608.View ArticlePubMedPubMed CentralGoogle Scholar
  29. Itman C, Loveland KL. Smads and cell fate: distinct roles in specification, development, and tumorigenesis in the testis. IUBMB Life. 2013;65:85–97.View ArticlePubMedGoogle Scholar
  30. Chen LY, Willis WD, Eddy EM. Targeting the Gdnf gene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development. Proc Natl Acad Sci U S A. 2016;113:1829–34.View ArticlePubMedPubMed CentralGoogle Scholar
  31. Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, et al. Mutations at a single codon in mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat Genet. 2012;44:85–8.View ArticleGoogle Scholar
  32. Vivante A, Kleppa MJ, Schulz J, Kohl S, Sharma A, Chen J, et al. Mutations in TBX18 cause dominant urinary tract malformations via transcriptional dysregulation of ureter development. Am J Hum Genet. 2015;97:291–301.View ArticlePubMedPubMed CentralGoogle Scholar
  33. Hwang DY, Kohl S, Fan X, Vivante A, Chan S, Dworschak GC, et al. Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract. Hum Genet. 2015;134:905–16.View ArticlePubMedPubMed CentralGoogle Scholar
  34. Kosfeld A, Kreuzer M, Daniel C, Brand F, Schäfer AK, Chadt A, et al. Whole-exome sequencing identifies mutations of TBC1D1 encoding a Rab-GTPase-activating protein in patients with congenital anomalies of the kidneys and urinary tract (CAKUT). Hum Genet. 2016;135:69–87.View ArticlePubMedGoogle Scholar


© The Author(s). 2017