CEP250 – Retinitis Pigmentosa

Centrosomal protein gene CEP250 encodes C-Nap1, a key component of centrosome cohesion in photoreceptors. Retinitis pigmentosa (MONDO:0019200) is a genetically heterogeneous retinal dystrophy marked by progressive photoreceptor loss.

Autosomal recessive loss-of-function variants in CEP250 have been identified in multiple families with nonsyndromic and syndromic retinitis pigmentosa. In an Iranian family, homozygous c.3463C>T (p.Arg1155Ter) segregated with early-onset severe and mild RP in four affected individuals (PMID:24780881). A consanguineous pedigree harbored homozygous c.562C>T (p.Arg188Ter) in a single nonsyndromic RP proband (PMID:30998843). In a Brazilian cohort, two additional probands carried frameshift alleles c.5383dup (p.Glu1795fs) and c.5050del (p.Asp1684fs) in syndromic RP cases (PMID:38674450). Segregation of CEP250 variants was confirmed in five affected relatives within the Iranian family (PMID:24780881).

All reported CEP250 alleles are predicted null (nonsense, frameshift, or canonical splice-site) and consistent with a loss-of-function mechanism. No recurrent or founder variants have been documented, and carrier frequencies are unavailable.

Functional studies demonstrate that homozygous p.Arg188Ter knockin mice exhibit severe reductions in retinal thickness and electroretinogram responses, mirroring human RP (PMID:30998843). Additionally, patient-derived missense p.Ala609Val fibroblasts show disrupted cilia formation, underscoring impaired centrosome cohesion as the pathogenic mechanism (PMID:28005958).

No conflicting reports have been published disputing CEP250 in RP. Further cell and animal model data exist beyond current ClinGen scoring.

Key take-home: Autosomal recessive CEP250 loss-of-function variants cause retinitis pigmentosa with clear segregation and functional concordance, supporting inclusion of CEP250 in AR RP gene panels.

References

• Journal of medical genetics • 2014 • A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome. PMID:24780881
• Human mutation • 2019 • Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa. PMID:30998843
• Genes • 2024 • Syndromic Retinitis Pigmentosa: A 15-Patient Study. PMID:38674450
• PloS one • 2016 • Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing. PMID:28005958

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