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
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.