TNXB Mutations Can Cause Vesicoureteral Reflux

Gbadegesin, Rasheed; Brophy, Patrick D.; Adeyemo, Adebowale; Hall, Gentzon; Gupta, Indra R.; Hains, David S.; Bartkowiak, Bartlomeij; Rabinovich, C. Egla; Chandrasekharappa, Settara C.; Homstad, Alison; Westreich, Katherine D.; Wu, Guanghong; Liu, Yutao; Holanda, Danniele G.; Clarke, Jason; Lavin, Peter; Selim, Angelica; Miller, Sara; Wiener, John S.; Ross, Scott E.; Foreman, John W.; Rotimi, Charles N.; Winn, Michelle P.

doi:10.1681/asn.2012121148

Cited by 63 publications

(74 citation statements)

References 42 publications

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“…5,6 Twentythree autosomal dominant genes have been identified to cause isolated CAKUT, with TNXB, WNT4, and DSTYK being the most recent ones. [7][8][9][10] According to the Mouse Genome Informatics database (http://www.informatics.jax.org), 1768 monogenic mouse models for CAKUT have been described, many of which are recessive and do not have a human disease correlate.…”

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confidence: 99%

Mild Recessive Mutations in Six Fraser Syndrome–Related Genes Cause Isolated Congenital Anomalies of the Kidney and Urinary Tract

Kohl

Hwang

Dworschak

et al. 2014

Journal of the American Society of Nephrology

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Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately 40% of children with ESRD in the United States. Hitherto, mutations in 23 genes have been described as causing autosomal dominant isolated CAKUT in humans. However, .90% of cases of isolated CAKUT still remain without a molecular diagnosis. Here, we hypothesized that genes mutated in recessive mouse models with the specific CAKUT phenotype of unilateral renal agenesis may also be mutated in humans with isolated CAKUT. We applied next-generation sequencing technology for targeted exon sequencing of 12 recessive murine candidate genes in 574 individuals with isolated CAKUT from 590 families. In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. We show that isolated CAKUT may be caused partially by mutations in recessive genes. Our results also indicate that biallelic missense mutations in the Fraser/MOTA/BNAR spectrum genes cause isolated CAKUT, whereas truncating mutations are found in the multiorgan form of Fraser syndrome. The newly identified recessive biallelic mutations in these six genes represent the molecular cause of isolated CAKUT in 2.5% of the 590 affected families in this study.

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confidence: 99%

Mild Recessive Mutations in Six Fraser Syndrome–Related Genes Cause Isolated Congenital Anomalies of the Kidney and Urinary Tract

Kohl

Hwang

Dworschak

et al. 2014

Journal of the American Society of Nephrology

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“…We have previously reported that VUR co-segregates with joint hypermobility in a family with TNXB mutation [9]. To provide further evidence that the rare variants identified by us are likely to be pathogenic, we performed joint hypermobility testing on three individuals with rare variants in TNXB .…”

Section: Resultsmentioning

confidence: 98%

“…We have previously reported two of these variants {c.9770C>T (T3257I) and c.3991G>A (G1331R) in families 6606 and 6952 respectively} [9]. All the TNXB variants were annotated using the transcript ENST00000375244 (Supplementary Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…It is therefore not surprising that most of the loci that have been reported in the literature are from relatively small pedigrees, yielding findings that are inconclusive. We recently reported segregating mutations in the TNXB gene in a large kindred with PVUR and joint hypermobility [9]. The tenascin genes are a class of extracellular matrix proteins with a relatively similar structure comprising N-terminal assembly and C-terminal fibrinogen-like domains, epidermal growth factor (EGF)-like repeats, and fibronectin III domains [10-12].…”

Section: Introductionmentioning

confidence: 99%

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Rare variants in tenascin genes in a cohort of children with primary vesicoureteric reflux

et al. 2015

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Background Primary vesicoureteral reflux (PVUR) is the most common malformation of the kidney and urinary tract and reflux nephropathy is a major cause of chronic kidney disease in children. Recently, we reported mutations in tenascin XB (TNXB) as a cause of PVUR with joint hypermobility. Methods To define the role of rare variants in tenascin genes in the etiology of PVUR, we screened a cohort of patients with familial PVUR (FPVUR) and non-familial PVUR (NFPVUR) for rare missense variants in TNXB and tenascin C (TNC) genes after excluding mutations in ROBO2 and SOX17. Results We identified 134 individuals from 112 families with PVUR, we excluded two families with mutations in ROBO2. We found rare missense variants in TNXB in the remaining 110 families comprising of 5/55 (9%) of families with FPVUR and 2/55 (4%) of NFPVUR. There were no differences in high-grade reflux, or renal parenchymal scarring between patients with and without TNXB variants. All patients with TNXB rare variants that were tested exhibited joint hypermobility. Overall we were able to identify causes of FPVUR in 7/57 (12%) families (9% in TNXB and 3% in ROBO2). Conclusions In conclusion, a rare missense variant in TNXB in combination with a positive family history of VUR and joint hypermobility may represent a non-invasive method to diagnose PVUR and warrants further evaluation in other cohorts.

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“…In humans, most CAKUT-causing genes reported to date exhibit an autosomal dominant mode of inheritance with variable expressivity and incomplete penetrance (Gbadegesin et al 2013; Hwang et al 2014; McPherson et al 1987; Sanna-Cherchi et al 2013). Nevertheless, mutations in seven recessive CAKUT-causing genes have recently been discovered (Humbert et al 2014; Kohl et al 2014; Saisawat et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Mutations of the SLIT2–ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract

et al. 2015

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Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40–50% of chronic kidney disease that manifests in the first two decades of life. Thus far, 31 monogenic causes of isolated CAKUT have been described, explaining ~12% of cases. To identify additional CAKUT-causing genes, we performed whole exome sequencing followed by a genetic burden analysis in 26 genetically unsolved families with CAKUT. We identified two heterozygous mutations in SRGAP1 in 2 unrelated families. SRGAP1 is a small GTPase activating protein in the SLIT2-ROBO2 signaling pathway, which is essential for development of the metanephric kidney. We then examined the pathway-derived candidate gene SLIT2 for mutations in cohort of 749 individuals with CAKUT and we identified 3 unrelated individuals with heterozygous mutations. The clinical phenotypes of individuals with mutations in SLIT2 or SRGAP1 were cystic dysplastic kidneys, unilateral renal agenesis, and duplicated collecting system. We show that SRGAP1 is expressed in early mouse nephrogenic mesenchyme and that it is coexpressed with ROBO2 in SIX2-positive nephron progenitor cells of the cap mesenchyme in developing rat kidney. We demonstrate that the newly identified mutations in SRGAP1 lead to an augmented inhibition of RAC1 in cultured human embryonic kidney cells and that the SLIT2 mutations compromise the ability of the SLIT2 ligand to inhibit cell migration. Thus, we report on two novel candidate genes for causing monogenic isolated CAKUT in humans.

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TNXB Mutations Can Cause Vesicoureteral Reflux

Cited by 63 publications

References 42 publications

Mild Recessive Mutations in Six Fraser Syndrome–Related Genes Cause Isolated Congenital Anomalies of the Kidney and Urinary Tract

Mild Recessive Mutations in Six Fraser Syndrome–Related Genes Cause Isolated Congenital Anomalies of the Kidney and Urinary Tract

Rare variants in tenascin genes in a cohort of children with primary vesicoureteric reflux

Mutations of the SLIT2–ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract

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