TNXB mutations can cause vesicoureteral reflux

Area of Science:

• Genetics
• Urology
• Molecular Biology

Background:

• Primary vesicoureteral reflux (VUR) is a frequent congenital anomaly of the kidney and urinary tract.
• VUR is a significant risk factor for pyelonephritic scarring and chronic kidney disease (CKD) in children.
• While heritability is suggested, specific genetic causes of VUR remain largely unknown.

Purpose of the Study:

• To identify the genetic basis of hereditary primary vesicoureteral reflux (VUR).

Main Methods:

• Genome-wide linkage analysis and whole-exome sequencing were performed on a family with hereditary VUR.
• Mutation analysis was conducted in a second family with a pathogenic TNXB variant.
• Fibroblast cell line studies assessed the functional impact of the identified mutation.
• Immunohistochemistry examined TNXB expression in the human ureterovesical junction.

Main Results:

• A significant linkage signal was found on chromosome 6p, leading to the identification of a heterozygous mutation (T3257I) in the tenascin XB (TNXB) gene.
• This TNXB mutation segregated with VUR in the studied family and was also observed with another pathogenic variant in a separate family.
• The T3257I mutation impaired fibroblast cell motility and reduced phosphorylated focal adhesion kinase expression, indicating a focal adhesion defect.
• TNXB is expressed in the human uroepithelium at the ureterovesical junction, suggesting a role in its closure during voiding.

Conclusions:

• Mutations in the TNXB gene are a cause of hereditary primary vesicoureteral reflux (VUR).
• These findings elucidate a novel genetic etiology for VUR and highlight TNXB's role in urinary tract development and function.