CEP290 – Leber Congenital Amaurosis 10

Leber congenital amaurosis type 10 (LCA10) is an autosomal recessive ciliopathy presenting with congenital severe visual impairment, extinguished electroretinogram responses, and nystagmus. CEP290 loss-of-function underlies the disease through disruption of photoreceptor ciliary transport and outer segment formation.

The deep intronic founder variant c.2991+1655A>G was identified homozygously and in compound heterozygosity with truncating CEP290 alleles in seven unrelated LCA10 probands (PMID:30114557). Additional biallelic nonsense and frameshift CEP290 mutations have been described in multiple cohorts, confirming a consistent genotype–phenotype correlation.

Mechanistically, c.2991+1655A>G creates a cryptic splice donor site, resulting in insertion of a pseudoexon (exon X) and frameshift. Antisense oligonucleotide (AON) therapy efficiently excludes exon X in patient-derived cells, restores full-length CEP290 protein, and rescues ciliary defects (PMID:27106101). In humanized mouse models, intravitreal AON delivery yields durable splicing correction without retinal toxicity.

CRISPR/Cas9-mediated excision of the intronic mutation in engineered 293FT cells and mouse retina reinstates wild-type CEP290 expression and normal ciliation, demonstrating the feasibility of genome editing for LCA10 (PMID:28109959).

A zebrafish cep290 knockdown model showed that expression of the human CEP290 N-terminal region alone rescues visual behavior and photoreceptor structure, delineating key functional domains for potential gene augmentation strategies (PMID:21257638).

Together, these data provide strong genetic evidence and moderate experimental concordance supporting a loss-of-function mechanism for CEP290 in LCA10. Molecular diagnosis of c.2991+1655A>G and truncating CEP290 variants is critical for early diagnosis, carrier screening, and guiding emerging splice-modulating or genome-editing therapies.

References

• Molecular therapy. Nucleic acids • 2018 • Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models. PMID:30114557
• Human molecular genetics • 2016 • In vitro and in vivo rescue of aberrant splicing in CEP290-associated LCA by antisense oligonucleotide delivery. PMID:27106101
• Molecular therapy : the journal of the American Society of Gene Therapy • 2017 • CRISPR/Cas9-Mediated Genome Editing as a Therapeutic Approach for Leber Congenital Amaurosis 10. PMID:28109959
• Human molecular genetics • 2011 • The N-terminal region of centrosomal protein 290 (CEP290) restores vision in a zebrafish model of human blindness. PMID:21257638

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