WDR19 – Nephronophthisis 13

Nephronophthisis 13 (NPHP13) is an autosomal recessive ciliopathy characterized by progressive renal fibrosis, impaired concentrating ability and hepatic ductal plate malformations (Caroli disease). WDR19 encodes the IFT144 subunit of the intraflagellar transport A (IFT-A) complex, essential for primary cilium assembly and function.

In a cohort of 36 children with hepatorenal fibrocystic diseases, NPHP13 was diagnosed in 11/36 (30.6%) cases, second only to ARPKD ([PMID:26260382]). Targeted exome sequencing of 48 unrelated patients with clinical nephronophthisis revealed WDR19 mutations in 3/48 (6.3%) index cases; subsequent Sanger sequencing identified a fourth family, yielding a total of four unrelated families and six affected individuals with NPHP13 ([PMID:25726036]).

All patients harbored biallelic WDR19 variants, most notably the recurrent missense change c.3533G>A (p.Arg1178Gln) in trans with second pathogenic alleles. Familial segregation included two affected siblings with c.3533G>A (p.Arg1178Gln), confirming autosomal recessive inheritance ([PMID:25726036]).

Functional assessment showed diffuse cytoplasmic staining of WDR19 in patient kidney biopsies versus luminal border localization in controls, indicating mislocalization in NPHP13 kidney tissue ([PMID:25726036]). In Caenorhabditis elegans, loss of the WDR19 orthologue DYF-2 disrupts IFT-A assembly and cilium motility, recapitulating ciliopathy phenotypes and demonstrating evolutionary conservation of pathogenic mechanisms ([PMID:16957054]).

The convergence of genetic segregation, a recurrent missense variant, and concordant functional studies supports a mechanism whereby WDR19 loss-of-function impairs intraflagellar transport, driving renal cystogenesis, fibrosis and ductal plate malformations in NPHP13.

Further large-scale screenings and in vitro rescue assays will refine the allelic spectrum and may inform targeted therapies for WDR19-related nephronophthisis. Key Take-home: Biallelic WDR19 variants cause autosomal recessive NPHP13 and should be included in diagnostic gene panels for cystic kidney and Caroli disease.

References

• Pediatric nephrology (Berlin, Germany) • 2016 • Hepatorenal fibrocystic diseases in children. PMID:26260382
• Pediatric nephrology (Berlin, Germany) • 2015 • Nephronophthisis 13: implications of its association with Caroli disease and altered intracellular localization of WDR19 in the kidney. PMID:25726036
• Molecular biology of the cell • 2006 • Caenorhabditis elegans DYF-2, an orthologue of human WDR19, is a component of the intraflagellar transport machinery in sensory cilia. PMID:16957054

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