Description of Two Siblings with Apparently Severe CEP290 Mutations and Unusually Mild Retinal Disease Unrelated to Basal Exon Skipping or Nonsense-Associated Altered Splicing

Abstract

CEP290 mutations cause a spectrum of ciliopathies, including Leber congenital amaurosis. Milder retinal diseases have been ascribed to exclusion of CEP290 mutant exons through basal exon skipping (BES) and/or nonsense-associated altered splicing (NAS). Here, we report two siblings with some preserved vision despite biallelism for presumably severe CEP290 mutations: a maternal splice site change in intron 18 (c.1824 + 3A > G) and a paternal c.6869dup (p.Asn2290Lysfs∗6) in exon 50 that introduces a premature termination codon (PTC) within the same exon. Analyzing mRNAs from fibroblasts of the two siblings, we detected no BES or NAS which could have enabled the production of PTC-free CEP290 isoforms from the paternal allele. In contrast, we reveal partial alteration of exon 18 donor splice site, allowing the transcription of some correctly spliced CEP290 mRNAs from the maternal allele which likely account for the mild retinal disease. This observation adds further variability to the mechanisms underlying CEP290 pleiotropy.