ORPHA: 289365; DO: 9620;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.33-p21.32 | Vesicoureteral reflux 8 | 615963 | Autosomal dominant | 3 | TNXB | 600985 |
A number sign (#) is used with this entry because vesicoureteral reflux-8 (VUR8) is caused by heterozygous mutation in the TNXB gene (600985) on chromosome 6p21.
For a general phenotypic description and a discussion of genetic heterogeneity of vesicoureteral reflux, see VUR1 (193000).
Gbadegesin et al. (2013) reported a large 5-generation family in which 9 individuals had radiologically confirmed vesicoureteral reflux and/or duplex collecting systems. Two affected mutation carriers who were examined showed signs of asymptomatic joint hypermobility.
The transmission pattern of VUR8 in the family reported by Gbadegesin et al. (2013) was consistent with autosomal dominant inheritance.
By genomewide linkage analysis of a large family with VUR, Gbadegesin et al. (2013) found linkage to chromosome 6p (multipoint parametric lod score of 3.3).
In affected members of a 5-generation family with vesicoureteral reflux, Gbadegesin et al. (2013) identified a heterozygous missense mutation in the TNXB gene (T3257I; 600985.0006). The mutation was found by a combination of linkage analysis and whole-exome sequencing. Compared to controls, patient fibroblasts showed significantly impaired migration in a wound-healing assay; this was associated with decreased expression of phosphorylated FAK (600758). These findings suggested that the mutation caused a defect in the focal adhesions that link the cell cytoplasm to the extracellular matrix, with persistent and enhanced cell adhesion. Immunohistochemical studies showed that the human uroepithelial lining of the ureterovesical junction expresses TNXB, suggesting that TNXB may be important for generating tensile forces that close the ureterovesical junction during voiding. Gbadegesin et al. (2013) postulated a gain-of-function effect of the mutation. Screening of the TNXB gene in 11 probands with VUR identified 1 patient with a heterozygous missense mutation (G1331R; 600985.0007). Functional studies of this variant or of patient cells were not performed. This patient's sister had a history of recurrent urinary tract infections, but DNA samples and imaging were not available.
Gbadegesin, R. A., Brophy, P. D., Adeyemo, A., Hall, G., Gupta, I. R., Hains, D., Bartkowiak, B., Rabinovich, C. E., Chandrasekharappa, S., Homstad, A., Westreich, K., Wu, G., and 11 others. TNXB mutations can cause vesicoureteral reflux. J. Am. Soc. Nephrol. 24: 1313-1322, 2013. [PubMed: 23620400] [Full Text: https://doi.org/10.1681/ASN.2012121148]