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
| Autor: | Eric Olinger, Miguel Barroso-Gil, Simon A. Ramsbottom, Elisa Molinari, John A. Sayer, Colin G. Miles |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
antisense oligonucleotide Meckel syndrome precision medicine Gene Expression Cell Cycle Proteins 030105 genetics & heredity Biology QH426-470 medicine.disease_cause CC2D2A Ciliopathies Joubert syndrome 03 medical and health sciences Exon medicine CEP120 Genetics Humans Genetic Predisposition to Disease Molecular Biology Alleles Genetic Association Studies Genetics (clinical) Mutation Genetic heterogeneity Gene Expression Profiling Original Articles Exons Genetic Therapy Oligonucleotides Antisense medicine.disease Exon skipping 3. Good health Cytoskeletal Proteins Ciliopathy Phenotype 030104 developmental biology ciliopathy Genetic Loci Organ Specificity Original Article exon skipping |
| Zdroj: | Molecular Genetics & Genomic Medicine, Vol 9, Iss 12, Pp n/a-n/a (2021) Molecular Genetics & Genomic Medicine |
| ISSN: | 2324-9269 |
| Popis: | Background 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 tissue‐specific preservation of the amount of expressed functional protein. Methods We systematically reviewed and annotated genetic variants and clinical presentations reported in CEP120‐ and CC2D2A‐associated disease and we combined in silico and ex vivo approaches to study tissue‐specific transcripts and identify molecular targets for exon skipping. Results We confirmed more severe clinical presentations associated with truncating CC2D2A mutations. We identified and confirmed basal exon skipping in the kidney, with possible relevance for organ‐specific disease manifestations. Finally, we proposed a multimodal approach to classify exons amenable to exon skipping. 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. Conclusion Genotype‐phenotype correlations for CC2D2A support the deleteriousness of null alleles and CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches. Mutations in CEP120 and CC2D2A cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. Here we 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 and propose a multimodal approach to classify exons amenable to exon skipping. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |