title: TNXB mutations can cause vesicoureteral reflux.
abstract: Primary vesicoureteral reflux (VUR) is the most common congenital anomaly of the kidney and the urinary tract, and it is a major risk factor for pyelonephritic scarring and CKD in children. Although twin studies support the heritability of VUR, specific genetic causes remain elusive. We performed a sequential genome-wide linkage study and whole-exome sequencing in a family with hereditary VUR. We obtained a significant multipoint parametric logarithm of odds score of 3.3 on chromosome 6p, and whole-exome sequencing identified a deleterious heterozygous mutation (T3257I) in the gene encoding tenascin XB (TNXB in 6p21.3). This mutation segregated with disease in the affected family as well as with a pathogenic G1331R change in another family. Fibroblast cell lines carrying the T3257I mutation exhibited a reduction in both cell motility and phosphorylated focal adhesion kinase expression, suggesting a defect in the focal adhesions that link the cell cytoplasm to the extracellular matrix. Immunohistochemical studies revealed 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. Taken together, these results suggest that mutations in TNXB can cause hereditary VUR.
authors.affiliation: Divisions of Nephrology, Duke University Medical Center, Durham, NC 27710, USA. rasheed.gbadegesin@duke.edu
authors.forename: Rasheed A
authors.initials: RA
authors.lastname: Gbadegesin
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Brophy
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adeyemo
authors.forename: Gentzon
authors.initials: G
authors.lastname: Hall
authors.forename: Indra R
authors.initials: IR
authors.lastname: Gupta
authors.forename: David
authors.initials: D
authors.lastname: Hains
authors.forename: Bartlomeij
authors.initials: B
authors.lastname: Bartkowiak
authors.forename: C Egla
authors.initials: CE
authors.lastname: Rabinovich
authors.forename: Settara
authors.initials: S
authors.lastname: Chandrasekharappa
authors.forename: Alison
authors.initials: A
authors.lastname: Homstad
authors.forename: Katherine
authors.initials: K
authors.lastname: Westreich
authors.forename: Guanghong
authors.initials: G
authors.lastname: Wu
authors.forename: Yutao
authors.initials: Y
authors.lastname: Liu
authors.forename: Danniele
authors.initials: D
authors.lastname: Holanda
authors.forename: Jason
authors.initials: J
authors.lastname: Clarke
authors.forename: Peter
authors.initials: P
authors.lastname: Lavin
authors.forename: Angelica
authors.initials: A
authors.lastname: Selim
authors.forename: Sara
authors.initials: S
authors.lastname: Miller
authors.forename: John S
authors.initials: JS
authors.lastname: Wiener
authors.forename: Sherry S
authors.initials: SS
authors.lastname: Ross
authors.forename: John
authors.initials: J
authors.lastname: Foreman
authors.forename: Charles
authors.initials: C
authors.lastname: Rotimi
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Winn
mesh_terms: D002448:Cell Adhesion / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA; D019063:Tenascin / Q000235:genetics* / Q000378:metabolism; D014551:Urinary Tract / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D014718:Vesico-Ureteral Reflux / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D019063:Tenascin; C081865:tenascin X