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Update of genetic variants in CEP120 and CC2D2A -- with an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies
  • +3
  • Miguel Barroso-Gil,
  • Eric Olinger,
  • Simon Ramsbottom,
  • Elisa Molinari,
  • Colin Miles,
  • John Sayer
Miguel Barroso-Gil
Newcastle University
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Eric Olinger
Newcastle University
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Simon Ramsbottom
Newcastle University
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Elisa Molinari
Newcastle University
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Colin Miles
Newcastle University
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John Sayer
Newcastle University
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Abstract

Mutations in ciliary genes cause a spectrum of both overlapping and distinct clinical syndromes (ciliopathies). CEP120 and CC2D2A are paradigmatic examples for this genetic heterogeneity and pleiotropy as mutations in both cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. The molecular basis for this phenotypical variability is not understood but basal exon skipping likely contributes to tolerance for deleterious mutations via preservation of the amount of expressed functional protein. Here we systematically review and annotate genetic variants described in CEP120- and CC2D2A-associated disease and confirm more severe clinical presentations with biallelic truncating CC2D2A mutations. Combining in silico and ex vivo studies, we identify alternative basal exon skipping in the kidney, with possible relevance for organ-specific disease manifestations. Finally, we propose a multimodal approach to classify exons amenable to exon skipping and by mapping reported variants, 14 truncating mutations in 7 CC2D2A exons were identified as potentially rescuable by targeted exon skipping, an approach that is already in clinical use for other inherited human diseases. We conclude that genotype-phenotype correlations for CC2D2A support the deleteriousness of null alleles and that CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches.