NEK8 – Autosomal Dominant Polycystic Kidney Disease

NEK8 (HGNC:13387) encodes a serine/threonine kinase localized to the proximal region of primary cilia. Autosomal dominant polycystic kidney disease (ADPKD, MONDO:0004691) is most commonly caused by PKD1 and PKD2 but recent studies implicate NEK8 heterozygous variants in a new AD form. A multi-center study published in 2023 identified monoallelic NEK8 kinase domain missense variants in individuals with early-onset cystic kidney disease (mostly neonatal) (PMID:37598857). A total of 21 probands from 12 unrelated families uniformly exhibited renal cystic disease without consistent extra-renal manifestations (PMID:37598857). The study also reported recurrent de novo p.Arg45Trp in 10 families, including somatic mosaicism, and additional kinase domain variants p.Ile150Met and p.Lys157Gln. These findings expand the genetic heterogeneity of ADPKD.

Inheritance of NEK8-related ADPKD is autosomal dominant, evidenced by recurrent de novo and familial kinase-domain missense events. In the Kidney International cohort, monoallelic missense variants clustered within the NEK8 kinase domain, notably p.Arg45Trp in ten families, and p.Ile150Met and p.Lys157Gln in two additional pedigrees (PMID:37598857). An independent cohort from the Irish Kidney Gene Project identified NEK8 heterozygotes in 3 families and linked these variants to earlier progression to kidney failure compared to other non-PKD1 ADPKD causes (PMID:39881088). These 15 families collectively highlight a recurrent mutational spectrum and an earlier renal phenotype in NEK8-ADPKD.

Segregation analysis across 12 families demonstrated co-segregation of NEK8 kinase domain variants with cystic kidney phenotypes, including vertical transmission in multiple pedigrees (PMID:37598857).

Functional studies in patient-derived fibroblasts and tubuloids, as well as Nek8-knockout IMCD3 cells, demonstrated that NEK8 variants localize normally to proximal cilia and support ciliogenesis but exert dominant-negative effects. Specifically, IMCD3 cells expressing p.Arg45Trp or p.Lys157Gln showed significantly reduced ciliary polycystin-2 levels with preserved ANKS6 localization (PMID:37598857). In vitro kinase assays revealed markedly decreased enzymatic activity for p.Arg45Trp NEK8. Additionally, cells harboring this variant displayed increased DNA damage signaling, consistent with impaired NEK8-mediated genomic maintenance. These data support a dominant-negative mechanism for NEK8 kinase domain missense variants in ADPKD.

Biallelic NEK8 pathogenic variants are known to cause autosomal recessive ciliopathies such as nephronophthisis and renal-hepatic-pancreatic dysplasia, often with multi-organ involvement (PMID:26697755; PMID:18199800). Unlike these syndromic presentations, heterozygous kinase domain mutations produce a kidney-restricted ADPKD phenotype without extrarenal features in the majority of cases (PMID:37598857). No studies have refuted the association of NEK8 missense variants with ADPKD to date.

Collectively, robust genetic evidence including 21 unrelated probands, segregation in 12 families, and replication in an independent cohort, combined with concordant functional assays, support a Strong clinical validity for NEK8 in ADPKD. The autosomal dominant inheritance, recurrent de novo events, and dominant-negative mechanism align with ClinGen criteria for Strong gene-disease association. Incorporating NEK8 into ADPKD gene panels may facilitate diagnosis and prognosis, particularly for early-onset or rapidly progressive cases. Future studies should define the full phenotypic spectrum and assess potential genotype-based therapeutic interventions. Key Take-home: Heterozygous NEK8 kinase domain missense variants constitute a novel cause of autosomal dominant PKD via a dominant-negative mechanism, with direct implications for genetic testing and patient management.

References

• Kidney International • 2023 • Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease. PMID:37598857
• Irish Kidney Gene Project observational cohort • 2024 • Disease progression and genetic spectrum in ADPKD families PMID:39881088
• 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
• Journal of the American Society of Nephrology • 2008 • NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis. PMID:18199800

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