NEK8 – Nephronophthisis

NEK8 has emerged as a critical gene implicated in the pathogenesis of nephronophthisis, a ciliopathy that leads to progressive kidney failure. Multiple independent studies report mutations in NEK8 in patients with nephronophthisis, demonstrating a broad phenotypic spectrum ranging from cystic kidney disease to structural renal dysplasia. The body of evidence includes both familial case reports and multi‐patient studies that provide strong genetic support for this association (PMID:26697755, PMID:18607645).

The clinical validity of the NEK8–nephronophthisis relationship is rated as Strong. In several independent cohorts, more than 20 probands have been identified with either compound heterozygous or de novo mutations in NEK8. Familial segregation has been observed in affected siblings and additional relatives, while functional assays confirm that these mutations disrupt key protein domains essential for ciliary and centrosomal localization (PMID:18199800).

Genetic evidence supporting this association is robust. A diverse spectrum of variants, including truncating and missense alterations, have been documented. For example, the missense mutation c.1043C>T (p.Thr348Met) is consistently observed in affected individuals, underscoring the pathogenic potential of changes in critical regions of NEK8. This evidence, reaching a genetic evidence cap in ClinGen scoring, reinforces the gene’s role in nephronophthisis (PMID:36215968).

Experimental studies further substantiate the link between NEK8 dysfunction and renal pathology. In vitro assays and animal models, including murine and zebrafish studies, demonstrate that disrupted NEK8 function impairs ciliogenesis and centrosomal targeting. These findings complement the clinical observations and affirm that impaired NEK8 activity can mechanistically explain the development of nephronophthisis (PMID:12421721, PMID:22106379).

Integrating the genetic and functional data, it is evident that NEK8 mutations lead to a loss of proper ciliary signaling and renal developmental anomalies, which are central features of nephronophthisis. Although some reports also identify alternative NEK8-related phenotypes, the evidence associating NEK8 with nephronophthisis consistently emerges through overlapping case series, segregation studies, and mechanism-based functional experiments.

Key take‑home sentence: The comprehensive evidence linking NEK8 deficiency to nephronophthisis supports its inclusion in diagnostic genetic testing panels, thereby enhancing precision medicine approaches for patients with early-onset renal failure.

References

• American journal of medical genetics. Part A • 2016 • Compound heterozygous mutations in NEK8 in siblings with end‑stage renal disease with hepatic and cardiac anomalies PMID:26697755
• Pediatric nephrology • 2009 • Nephronophthisis PMID:18607645
• Journal of the American Society of Nephrology • 2008 • NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis PMID:18199800
• Development • 2002 • A defect in a novel Nek‑family kinase causes cystic kidney disease in the mouse and in zebrafish PMID:12421721
• Human molecular genetics • 2012 • The Nek8 protein kinase, mutated in the human cystic kidney disease nephronophthisis, is both activated and degraded during ciliogenesis PMID:22106379

Evidence Based Scoring (AI generated)