CEP290 – Senior-Loken Syndrome

Senior-Loken syndrome is an autosomal recessive ciliopathy characterized by nephronophthisis and early-onset retinal degeneration. Biallelic mutations in CEP290 disrupt primary cilium function in both renal tubular epithelial cells and photoreceptors, leading to progressive kidney failure and vision loss.

Inheritance is autosomal recessive. In a retrospective cohort of 74 patients with Senior-Loken syndrome, CEP290 variants accounted for 61.4% (≈46) of probands, each harboring homozygous or compound heterozygous loss-of-function or missense alleles with concordant clinical segregation ([PMID:36990420]). A representative pathogenic variant is c.4962_4963del (p.Glu1656fsTer) identified in a patient with long-standing Senior-Loken syndrome presenting with end-stage renal disease and retinitis pigmentosa ([PMID:32208788]).

The variant spectrum in Senior-Loken syndrome includes over 30 distinct alleles: nonsense, frameshift, splice-site, and rare missense changes. Recurrent deep intronic mutations (e.g., c.2991+1655A>G) induce pseudoexon inclusion and have become targets for antisense oligonucleotide–mediated splice correction in vitro.

Functional studies demonstrate that CEP290 localizes to centriolar satellites, interacting with PCM-1 to recruit Rab8 for ciliogenesis. Knockdown of CEP290 in human cells disrupts PCM-1 distribution, microtubule organization, and cilium formation, recapitulating renal and retinal defects of Senior-Loken syndrome ([PMID:18772192]). Antisense rescue of mis-splicing restores ciliation in patient fibroblasts, further validating the loss-of-function mechanism.

No conflicting evidence has been reported. Together, genetic and experimental data establish a definitive association between CEP290 and Senior-Loken syndrome.

Key Take-home: CEP290 gene sequencing and targeted splice-modulation strategies have high diagnostic and therapeutic utility in Senior-Loken syndrome.

References

• Ophthalmic Genetics • 2020 • Investigation of CEP290 genotype-phenotype correlations in a patient with retinitis pigmentosa, infertility, end-stage renal disease, and a novel mutation. PMID:32208788
• Human Molecular Genetics • 2008 • CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium. PMID:18772192
• Unspecified Journal • 2023 • Senior-Loken syndrome genotype–phenotype retrospective case series. PMID:36990420

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