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CERKL
CERK like autophagy regulator
CERKL is located on the long (q) arm of chromosome 2, at band 2q31.3. Arm ratio per GRCh38 - banding schematic.
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Overview
CERKL (CERK like autophagy regulator) is located on chromosome 2 and encodes a 558-amino-acid protein that participates in autophagy, the cellular process by which damaged components are broken down and recycled. Despite its name suggesting similarity to ceramide kinase enzymes, CERKL functions primarily as a regulator of autophagy rather than as a kinase itself.
The protein appears to play a specialised role in photoreceptor cells, the light-detecting cells at the back of the eye that enable vision. Pathogenic variants in CERKL have been identified in individuals with inherited retinal conditions, where progressive photoreceptor degeneration leads to vision impairment. Understanding CERKL function may inform approaches to preserving retinal health in affected individuals.
What the gene does
The CERKL protein contributes to autophagy, a housekeeping process essential for maintaining cellular health by removing damaged proteins and organelles. This quality-control mechanism is particularly important in photoreceptor cells, which face continuous metabolic demands and oxidative stress due to their light-sensing function.
CERKL contains a diacylglycerol kinase catalytic domain (DAGKc) spanning amino acids 164 to 339, although the protein's primary function relates to autophagy regulation rather than lipid kinase activity. Research suggests CERKL may help coordinate the formation or maturation of autophagosomes, the membrane-bound structures that engulf cellular debris for degradation. The protein's presence in both the cytoplasm and nucleus, facilitated by nuclear localisation signals near the N-terminus, indicates it may integrate signals between cellular compartments to regulate autophagy in response to cellular stress.
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Chromosome location
CERKL is located on the long arm of chromosome 2 at position 31.3, designated as 2q31.3. The gene spans this chromosomal region and encodes a protein product of 558 amino acids. The genomic structure and precise exon count have not been extensively characterised in widely available databases, though the gene has been mapped with confidence to this locus through both genetic linkage studies and molecular analysis.
Protein structure
The CERKL protein comprises 558 amino acids with several functionally relevant regions. The N-terminal portion (amino acids 1-36) is predicted to be disordered, a structural feature often associated with regulatory flexibility. Two nuclear localisation signals are present: the first spanning amino acids 2 to 9 and the second at positions 102 to 106, enabling the protein to shuttle between the cytoplasm and nucleus.
The central region contains a DAGKc domain (diacylglycerol kinase catalytic domain) extending from amino acid 164 to 339. Despite this kinase-related domain, biochemical studies suggest CERKL functions primarily in autophagy regulation rather than as an active lipid kinase. The domain organisation indicates the protein may have evolved from ancestral kinases to adopt a specialised regulatory role in cellular quality control pathways.
Key variants
Pathogenic variants in CERKL have been documented across the coding sequence, including missense changes that alter single amino acids, nonsense variants that introduce premature stop codons, and small insertions or deletions that disrupt the reading frame. The functional impact of these variants generally involves impaired autophagy regulation, which may compromise photoreceptor cell survival over time. Variant interpretation requires consideration of the specific amino acid change, its location relative to functional domains, and evidence from clinical and laboratory studies.
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.1050_1053del | p.Val351fs | Pathogenic | ★★☆☆ | Retinitis pigmentosa 26 |
c.1177C>T | p.Gln393Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa |
c.1227C>A | p.Cys409Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 26 |
c.271G>T | p.Glu91Ter | Pathogenic | ★★☆☆ | Retinitis pigmentosa 26 |
c.294_295del | p.Phe99fs | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 26 |
c.396del | p.Lys132fs | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 26 |
c.426_430del | p.Asn142fs | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 26 |
c.568del | p.Val190fs | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 26 |
c.678-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 26 |
c.93del | p.Leu32fs | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 26 |
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 CERKL are associated with inherited retinal disorders, a group of conditions characterised by progressive degeneration of photoreceptor cells leading to vision loss. These conditions typically follow autosomal recessive inheritance, meaning an affected individual carries pathogenic variants in both copies of the gene. The clinical presentation can vary, with some individuals experiencing early-onset vision problems whilst others retain useful vision into adulthood. Severity and progression depend on the specific variants involved and individual factors that may modify disease expression.
No disease links recorded for this gene in our reference set.
UK clinical status
CERKL is included in the NHS Genomic Medicine Service Retinal disorders panel with a green classification (version R32), indicating it is an established gene for diagnostic testing in individuals with inherited retinal conditions. This inclusion reflects evidence supporting a causal relationship between CERKL variants and retinal disease, making genetic testing for this gene available through the NHS for eligible patients meeting clinical criteria for retinal disorder evaluation.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the CERKL gene do in the eye?
CERKL produces a protein that helps maintain photoreceptor cells, the light-sensing cells in the retina, by supporting autophagy - the process cells use to clear damaged components. This housekeeping function appears particularly important for the long-term survival of these metabolically active cells.
How are CERKL variants inherited?
CERKL-related retinal conditions typically follow autosomal recessive inheritance, meaning an affected individual inherits a pathogenic variant from each parent. Parents who each carry one variant are generally unaffected but have a 25% chance with each pregnancy of having an affected child.
Is genetic testing for CERKL available on the NHS?
Yes, CERKL is included in the NHS Genomic Medicine Service Retinal disorders panel, making testing available for individuals who meet clinical criteria for inherited retinal disease evaluation. A healthcare provider can assess eligibility and arrange testing through appropriate NHS pathways.