ArticleKidney international2023
Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease.
Article in Kidney international, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 36 citations in OpenAlex.
- 'Missing' disease-causing variants in Alport syndrome.Nature reviews. Nephrology · 2026Review
- Monogenic Etiologies of Kidney Cysts in the Pediatric Population: An Observational Cohort Study.Clinical journal of the American Society of Nephrology : CJASN · 2026Observational
- Monogenic kidney disease and monogenic diabetes are present in renal clinic patients with non-genetic diagnoses.Scientific reports · 2026Article
- COBT: a gene-based rare variant burden test for case-only study designs using aggregated genotypes from public reference cohorts.Genome medicine · 2026Article
- Exome Sequencing in a Large Cohort with Ciliopathy-Related Kidney Disease.Clinical journal of the American Society of Nephrology : CJASN · 2026Article
- Typical and atypical ADPKD: predicted pathogenic genetic variants and population frequencies.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2026Article
- Characterization of Kidney and Liver Cystic Phenotype Associated with GANAB Using Advanced Imaging Biomarkers.Nephron · 2026Article
- Genomic and epigenomic landscape of ADPKD: towards precision diagnostics and tailored treatments.Frontiers in epigenetics and epigenomics · 2026Review
- Autosomal dominant polycystic kidney disease: an overview of recent genetic and clinical advances.Renal failure · 2025Review
- Genetic testing in autosomal dominant polycystic kidney disease: why it matters in 2025.Clinical kidney journal · 2025Article
- Atypical presentations of fetal polycystic kidney disease demonstrates the utility of a genomic autopsy for accurate post-mortem diagnoses.Human genomics · 2025Article
- Overexpression of the NEK8 kinase inhibits homologous recombination.DNA repair · 2025Article
- Polycystic Kidney Disease in Children: The Current Status and the Next Horizon.American journal of kidney diseases : the official journal of the National Kidney Foundation · 2025Review
- Characterizing the ADPKD-Kidney international reports · 2025Article
- Article
- Functional Analysis of aKidney international reports · 2025Article
- Characteristics of patients with autosomal polycystic kidney disease reaching kidney failure by age 40.Pediatric nephrology (Berlin, Germany) · 2025Article
- Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.Journal of the American Society of Nephrology : JASN · 2025Article
- Review
- NEK8, a NIMA-family protein kinase at the core of the ciliary INV complex.Cell communication and signaling : CCS · 2025Review
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48 authors at 20 institutions in 8 countries.
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Abstract
Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD.
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