Mutations in ANKS6 cause a nephronophthisis-like phenotype with ESRD

Area of Science:

• Genetics
• Nephrology
• Developmental Biology

Background:

• Nephronophthisis (NPHP) is a leading genetic cause of chronic kidney disease (CKD), but its genetic basis remains unknown in over half of affected individuals.
• Identifying novel genetic factors is crucial for understanding NPHP pathogenesis and improving diagnostic capabilities.

Purpose of the Study:

• To identify the genetic cause of NPHP-like phenotypes in a consanguineous family.
• To investigate the role of the ANKS6 gene in kidney development and its association with NPHP.

Main Methods:

• Genome-wide analysis and targeted resequencing were performed on a Turkish multiplex family.
• ANKS6 variants were screened in a cohort of 56 unrelated patients with various kidney diseases.
• Immunohistochemistry and Western blotting were used to analyze ANKS6 expression and Wnt/β-catenin signaling in kidney tissues and rat models.

Main Results:

• A canonical splice site mutation in ANKS6 was identified in the affected family, segregating with an NPHP-like phenotype.
• Four additional ANKS6 variants were found in unrelated CKD patients, including those with NPHP, chronic glomerulonephritis, and interstitial nephritis.
• ANKS6 expression patterns change during human kidney development, and its mutations are associated with altered β-catenin levels in rat kidneys.

Conclusions:

• ANKS6 mutations are a cause of NPHP-like kidney disease in humans.
• ANKS6 plays a significant role in human kidney development.
• Dysregulation of ANKS6 may contribute to NPHP pathogenesis through mechanisms involving the Wnt/β-catenin pathway.