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NEK8
NIMA related kinase 8
NEK8 is located on the long (q) arm of chromosome 17, at band 17q11.2. Arm ratio per GRCh38 - banding schematic.
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Overview
NEK8 (NIMA related kinase 8) is located on chromosome 17q11.2 and encodes a protein of 692 amino acids. The protein functions as a serine/threonine kinase with a central role in regulating the assembly and maintenance of primary cilia, cellular antennae that sense environmental signals and coordinate developmental pathways. Disruption of NEK8 function impairs cilia structure, leading to defects in organ formation, particularly in the kidneys. Variants in this gene are associated with autosomal recessive renal ciliopathies, a group of conditions characterised by cystic kidney disease and developmental abnormalities. NEK8 is recognised on UK clinical diagnostic panels for cystic kidney disease and multisystem ciliopathy disorders.
What the gene does
NEK8 functions primarily in the construction and regulation of primary cilia, organelles that project from the cell surface and serve as sensory hubs for biochemical and mechanical signals. The protein localises to the base and along the length of cilia, where it phosphorylates target proteins involved in ciliary assembly and cargo transport. Through its kinase activity, NEK8 coordinates the intraflagellar transport system, a bidirectional movement mechanism that delivers structural components and signalling molecules along the cilium. Proper ciliary function is essential during embryonic kidney development, where cilia on renal tubule cells detect fluid flow and regulate tubule diameter. When NEK8 activity is compromised, cilia become structurally abnormal or fail to form, resulting in aberrant cell division orientation, tubule dilation, and cyst formation in renal tissue. The protein also participates in the regulation of cellular polarity and left-right axis determination during early development, processes that depend on intact ciliary signalling pathways.
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Chromosome location
NEK8 is positioned on the long arm of chromosome 17 at band 17q11.2. This chromosomal region spans approximately 1.5 megabases and contains multiple genes involved in developmental regulation and signal transduction. The precise genomic coordinates and exon structure contribute to the gene's regulatory complexity, though detailed exon count data for this gene remain under characterisation.
Protein structure
The NEK8 protein comprises 692 amino acids organised into functionally distinct regions. The N-terminal Protein kinase domain spans amino acids 4-258 and catalyses the transfer of phosphate groups to serine and threonine residues on substrate proteins, enabling downstream signalling events. A Disordered region extends from amino acids 277-301, likely providing structural flexibility that facilitates protein-protein interactions or regulatory modifications. The C-terminal portion contains five tandem RCC1 repeats: RCC1 1 (amino acids 312-350), RCC1 2 (amino acids 410-461), RCC1 3 (amino acids 462-513), RCC1 4 (amino acids 580-631), and RCC1 5 (amino acids 632-684). These RCC1 repeats adopt a beta-propeller fold architecture and are thought to mediate interactions with other ciliary proteins, facilitating the assembly of multiprotein complexes required for cilium stability and function.
Key variants
Pathogenic variants in NEK8 typically consist of loss-of-function mutations, including nonsense, frameshift, and splice-site alterations that abolish or severely reduce protein production. Missense variants affecting the kinase domain or RCC1 repeats can also impair enzymatic activity or disrupt protein interactions necessary for ciliary function. The inheritance pattern is predominantly autosomal recessive, meaning that affected individuals carry variants on both gene copies.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1330G>T | p.Glu444Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Renal-hepatic-pancreatic dysplasia 2 |
c.1359_1360del | p.His454fs | Pathogenic/Likely pathogenic | ★★☆☆ | Nephronophthisis 9 |
c.1401G>A | p.Trp467Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Renal-hepatic-pancreatic dysplasia 2 |
c.1418-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Nephronophthisis 9 |
c.1495C>T | p.Arg499Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Renal-hepatic-pancreatic dysplasia 2 |
c.1795C>T | p.Arg599Ter | Pathogenic/Likely pathogenic | ★★☆☆ | NEK8-related disorder |
c.379C>T | p.Arg127Ter | Pathogenic/Likely pathogenic | ★★☆☆ | NEK8-related disorder |
c.828-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Nephronophthisis 9 |
c.1395del | p.Phe465fs | Pathogenic | ★☆☆☆ | Nephronophthisis 9 |
c.67C>T | p.Arg23Ter | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in NEK8 cause autosomal recessive renal ciliopathies, a spectrum of kidney disorders characterised by cyst formation, renal dysfunction, and developmental anomalies. Clinical presentations range from severe perinatal forms with enlarged cystic kidneys detectable by prenatal ultrasound to milder childhood-onset disease with progressive renal impairment. Some individuals may also exhibit extrarenal features such as liver abnormalities or skeletal changes, reflecting the broader role of cilia in multiple organ systems. The severity and progression of kidney disease vary depending on the nature of the variants and residual protein function.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic NEK8 variants typically follow ar/ad inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
NEK8 is included on several NHS Genomic Medicine Service panels. The gene holds green classification status on the Cystic kidney disease panel, the DDG2P (Developmental Disorders Genotype-to-Phenotype) panel, the Fetal anomalies panel (evidence level R21), the Rare multisystem ciliopathy disorders panel, and the Renal ciliopathies panel. Green status indicates strong evidence supporting the gene-disease relationship and confirms that NEK8 testing is routinely offered through NHS diagnostic pathways for patients presenting with relevant clinical features.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern do NEK8 variants follow?
NEK8-related conditions are inherited in an autosomal recessive manner, meaning an individual must inherit a pathogenic variant from both parents to develop the associated kidney disorder. Carriers with one variant copy typically remain unaffected.
Why are cilia important for kidney health?
Cilia on kidney tubule cells detect fluid flow and mechanical signals, coordinating cell division and tubule architecture during development. When cilia are defective, these processes go awry, leading to tubule dilation and cyst formation that impair kidney function.
Is NEK8 testing available on the NHS?
Yes, NEK8 is included on multiple NHS Genomic Medicine Service panels for cystic kidney disease and ciliopathy disorders. Testing is available through NHS clinical genetics services for individuals meeting appropriate referral criteria.