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.

Publisher: John Wiley & Sons Country of Publication: United States NLM ID: 101603758 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2324-9269 (Electronic) Linking ISSN: 23249269 NLM ISO Abbreviation: Mol Genet Genomic Med Subsets: MEDLINE

Original Publication: [Hoboken, NJ] : John Wiley & Sons, [2013]-

Gene Expression* ; Genetic Association Studies* ; Genetic Predisposition to Disease* ; Mutation*; Cell Cycle Proteins/*genetics ; Ciliopathies/*genetics ; Cytoskeletal Proteins/*genetics; Ciliopathies/diagnosis ; Ciliopathies/therapy ; Genetic Therapy/methods ; Oligonucleotides, Antisense/genetics ; Oligonucleotides, Antisense/therapeutic use ; Alleles ; Exons ; Gene Expression Profiling ; Genetic Loci ; Humans ; Organ Specificity ; Phenotype ; Precision Medicine

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.
(© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Hum Mutat. 2010 May;31(5):E1319-31. (PMID: 20232449)
Adv Drug Deliv Rev. 2015 Jun 29;87:104-7. (PMID: 25980936)
J Med Genet. 2016 Sep;53(9):608-15. (PMID: 27208211)
FASEB J. 2019 Jan;33(1):1440-1455. (PMID: 30133325)
Clin Genet. 2019 Feb;95(2):329-333. (PMID: 30267408)
Neuron. 2007 Oct 4;56(1):79-93. (PMID: 17920017)
Front Pediatr. 2017 Nov 20;5:244. (PMID: 29209597)
Hum Mol Genet. 2015 Mar 1;24(5):1410-9. (PMID: 25361962)
Drug Metab Dispos. 2007 Mar;35(3):460-8. (PMID: 17172312)
Eur J Hum Genet. 2018 Dec;26(12):1791-1796. (PMID: 30002499)
Nat Genet. 2008 Dec;40(12):1413-5. (PMID: 18978789)
Pediatr Neurol. 2020 May;106:43-49. (PMID: 32139166)
Curr Opin Obstet Gynecol. 2017 Apr;29(2):85-94. (PMID: 28151755)
RNA. 2007 Oct;13(10):1609-24. (PMID: 17684229)
Science. 2015 Jan 23;347(6220):1260419. (PMID: 25613900)
Adv Drug Deliv Rev. 2015 Jun 29;87:46-51. (PMID: 25666165)
Sci Rep. 2019 Jul 25;9(1):10828. (PMID: 31346239)
J Med Genet. 2019 Apr;56(4):261-264. (PMID: 30120217)
Nat Genet. 2007 Jul;39(7):875-81. (PMID: 17558409)
Lancet Neurol. 2013 Sep;12(9):894-905. (PMID: 23870701)
Sci Rep. 2019 Apr 15;9(1):6037. (PMID: 30988386)
J Med Genet. 2011 Feb;48(2):105-16. (PMID: 21068128)
Annu Rev Genomics Hum Genet. 2006;7:125-48. (PMID: 16722803)
Cell. 2011 Sep 30;147(1):70-9. (PMID: 21962508)
Nat Commun. 2017 Aug 21;8(1):306. (PMID: 28824175)
Proc Natl Acad Sci U S A. 2018 Dec 4;115(49):12489-12494. (PMID: 30446612)
Methods Mol Biol. 2018;1828:141-150. (PMID: 30171539)
Clin Dysmorphol. 2020 Jan;29(1):10-16. (PMID: 31577543)
Genes (Basel). 2019 May 14;10(5):. (PMID: 31091803)
J Med Genet. 2016 Mar;53(3):208-14. (PMID: 26673778)
Hum Mutat. 2016 Jun;37(6):564-9. (PMID: 26931183)
Hum Mol Genet. 2016 Jun 15;25(12):2552-2563. (PMID: 27106101)
Nature. 2020 May;581(7809):434-443. (PMID: 32461654)
J Med Genet. 2010 Jan;47(1):8-21. (PMID: 19574260)
Kidney Int. 1995 Oct;48(4):1226-32. (PMID: 8569084)
Proc Natl Acad Sci U S A. 2020 Jan 14;117(2):1113-1118. (PMID: 31879347)
Ultrasound Obstet Gynecol. 2014 Dec;44(6):719-21. (PMID: 24706459)
Cold Spring Harb Perspect Biol. 2017 Mar 1;9(3):. (PMID: 27793968)
Sci Transl Med. 2015 Jun 10;7(291):291fs24. (PMID: 26062843)
J Pathol. 2017 Jan;241(2):294-309. (PMID: 27859258)
Hum Mol Genet. 2011 Jul 1;20(13):2524-34. (PMID: 21493627)
Hum Mutat. 2010 Oct;31(10):1097-108. (PMID: 20690115)
Cold Spring Harb Perspect Biol. 2015 Jan 05;7(1):a020412. (PMID: 25561720)
Transl Sci Rare Dis. 2019 Jul 04;4(1-2):25-49. (PMID: 31763177)
J Med Genet. 2016 May;53(5):338-47. (PMID: 26862157)
Nat Commun. 2014 Jun 20;5:4207. (PMID: 24947469)
Hum Mutat. 2009 Aug;30(8):E813-30. (PMID: 19466712)
Nucleic Acids Res. 2020 Jan 8;48(D1):D682-D688. (PMID: 31691826)
Genet Med. 2017 Aug;19(8):875-882. (PMID: 28125082)
Pediatr Neurol. 2020 Nov;112:10. (PMID: 32827857)
Nat Genet. 2020 Nov;52(11):1145-1150. (PMID: 33046855)
Nat Genet. 2016 Jan;48(1):4-6. (PMID: 26711108)
Hum Genome Var. 2015 Mar 26;2:15001. (PMID: 27082236)
Mol Med Rep. 2017 Jan;15(1):305-308. (PMID: 27959436)
J Med Genet. 2012 Feb;49(2):126-37. (PMID: 22241855)
Arch Pathol Lab Med. 2006 Aug;130(8):1236-8. (PMID: 16879033)
Nat Genet. 2011 Jul 03;43(8):776-84. (PMID: 21725307)
Nature. 2010 Jan 28;463(7280):457-63. (PMID: 20110989)
Antisense Nucleic Acid Drug Dev. 1998 Dec;8(6):451-8. (PMID: 9918109)
Hum Mutat. 2000;15(1):57-61. (PMID: 10612823)
Hum Genet. 2017 Jun;136(6):665-677. (PMID: 28349240)
F1000Res. 2017 May 12;6:669. (PMID: 28690834)
Am J Hum Genet. 2008 Jun;82(6):1361-7. (PMID: 18513680)
Drug Discov Today. 2019 Aug;24(8):1637-1643. (PMID: 30877076)
Annu Rev Pharmacol Toxicol. 2010;50:259-93. (PMID: 20055705)
PLoS Genet. 2015 Oct 20;11(10):e1005575. (PMID: 26485645)
Sci Transl Med. 2015 Jun 10;7(291):291ra97. (PMID: 26062849)
Am J Med Genet A. 2020 Jan;182(1):229-249. (PMID: 31710777)
BMC Med Genet. 2016 Jan 04;17:1. (PMID: 26729329)
Curr Biol. 2013 Jul 22;23(14):1360-6. (PMID: 23810536)
J Neuromuscul Dis. 2015 Sep 2;2(3):269-279. (PMID: 27858743)
Am J Hum Genet. 2008 Nov;83(5):559-71. (PMID: 18950740)
Neuron. 2002 Nov 14;36(4):555-8. (PMID: 12441045)
PLoS Genet. 2017 Dec 27;13(12):e1007150. (PMID: 29281629)
J Med Genet. 2015 Aug;52(8):514-22. (PMID: 26092869)
Nat Rev Mol Cell Biol. 2017 Sep;18(9):533-547. (PMID: 28698599)
Am J Hum Genet. 2008 Apr;82(4):1011-8. (PMID: 18387594)
Mol Ther Nucleic Acids. 2019 Dec 6;18:298-307. (PMID: 31610379)
Genet Med. 2020 Jun;22(6):1051-1060. (PMID: 32055034)
Hum Genome Var. 2014 Nov 06;1:14020. (PMID: 27081510)
Sci Transl Med. 2018 Apr 18;10(437):. (PMID: 29669851)
Nat Med. 2019 Feb;25(2):225-228. (PMID: 30559420)
J Cell Biol. 2010 Oct 18;191(2):331-46. (PMID: 20956381)
Bioinformatics. 2019 Jun 1;35(11):1978-1980. (PMID: 30376034)
Genome Biol. 2016 Nov 28;17(1):242. (PMID: 27894351)
Cilia. 2012 Oct 01;1(1):18. (PMID: 23351400)
Hum Mutat. 2009 Nov;30(11):1574-82. (PMID: 19777577)
J Med Genet. 2012 Oct;49(10):636-41. (PMID: 23012439)

213473/Z/18/Z United Kingdom WT_ Wellcome Trust; MC_PC_17168 United Kingdom MRC_ Medical Research Council

Keywords: CC2D2A; CEP120; Joubert syndrome; Meckel syndrome; antisense oligonucleotide; ciliopathy; exon skipping; precision medicine

0 (CC2D2A protein, human)
0 (CEP120 protein, human)
0 (Cell Cycle Proteins)
0 (Cytoskeletal Proteins)
0 (Oligonucleotides, Antisense)

Date Created: 20210124 Date Completed: 20220323 Latest Revision: 20250530

20260130

PMC8683696

10.1002/mgg3.1603

33486889