CERKL – Autosomal Recessive Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a progressive retinal dystrophy characterized by rod–cone degeneration and night blindness. CERKL encodes a ceramide kinase–like protein selectively expressed in the retina. Mutations in CERKL were first linked to nonsyndromic autosomal recessive RP in Spanish families, establishing CERKL as RP26 (7 families, 9 affected) (PMID:18515597). Subsequent cohorts have confirmed its role across diverse populations.

Genetic studies in 272 Spanish RP families identified the recurrent nonsense variant c.769C>T (p.Arg257Ter) as the sole CERKL mutation in typical RP cases (PMID:21151602). In an Indian cohort, 14 unrelated RP patients harbored biallelic LoF variants including c.967_968del (p.Met323fs) and c.769C>T (p.Arg257Ter) (14 patients) (PMID:32865075). A founder splice‐site mutation c.238+1G>A was observed in seven Yemenite Jewish families (carrier frequency 4.4%) causing early macular involvement (7 families) (PMID:18055789). A nonsense variant c.847C>T in a consanguineous Pakistani pedigree further supports allelic heterogeneity (PMID:32411380). All reports fit an autosomal recessive inheritance model.

The variant spectrum in ARCERKL‐RP is dominated by recurrent truncating alleles: c.769C>T (p.Arg257Ter) across Spain, India, and Pakistan, c.967_968del (p.Met323fs) in Indian patients, and splice‐site c.238+1G>A in Yemenite Jews. Novel indels such as c.1045_1046delAT (p.Ile349fs) have also been described, underscoring loss‐of‐function as the primary mechanism.

Biochemical assays revealed that CERKL lacks detectable ceramide kinase activity; the R257X protein fails to localize to nucleoli and accumulates in the nucleus, suggesting destabilization of subcellular trafficking (PMID:15708351). Overexpression studies demonstrate that wild‐type CERKL protects cultured cells from oxidative‐stress–induced apoptosis, a function lost in the R257X mutant (PMID:19158957).

Proteomic analyses identified interactions between CERKL and neuronal calcium sensor proteins (GCAP1, GCAP2, recoverin) in a cation‐dependent manner, linking CERKL to phototransduction and calcium signaling pathways (PMID:22678504). These functional data concord with the human phenotype of photoreceptor degeneration.

No studies to date have refuted the CERKL–RP association or implicated alternative inheritance. The consistency of homozygous LoF variants in multiple cohorts and convergence of molecular assays meet criteria for a definitive gene–disease relationship.

In conclusion, biallelic truncating CERKL variants cause autosomal recessive retinitis pigmentosa through loss‐of‐function, with a characteristic early maculopathy. Genetic testing for recurrent alleles like c.769C>T (p.Arg257Ter) is recommended for molecular diagnosis, carrier screening, and selection of future gene‐based therapies.

References

• Investigative ophthalmology & visual science • 2008 • CERKL mutations and associated phenotypes in seven Spanish families with autosomal recessive retinitis pigmentosa. PMID:18515597
• Investigative ophthalmology & visual science • 2007 • A common founder mutation of CERKL underlies autosomal recessive retinal degeneration with early macular involvement among Yemenite Jews. PMID:18055789
• Ophthalmic genetics • 2020 • CERKL mutation causing retinitis pigmentosa(RP) in Indian population - a genotype and phenotype correlation study. PMID:32865075
• Biochimica et biophysica acta • 2005 • Characterization of a ceramide kinase-like protein. PMID:15708351
• Molecular vision • 2009 • Overexpression of CERKL, a gene responsible for retinitis pigmentosa in humans, protects cells from apoptosis induced by oxidative stress. PMID:19158957
• Investigative ophthalmology & visual science • 2012 • Ceramide kinase-like (CERKL) interacts with neuronal calcium sensor proteins in the retina in a cation-dependent manner. PMID:22678504
• Human genome variation • 2020 • Mutations in CERKL and RP1 cause retinitis pigmentosa in Pakistani families. PMID:32411380

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