Alternative Splicing in CEP290 Mutant Cats Results in a Milder Phenotype Than LCA Patients

Overview

Journal Vet Ophthalmol

Specialties Ophthalmology
Veterinary Medicine

Date 2022 Dec 10

PMID 36495011

Authors

Andrea L Minella

Kristina Narfstrom Wiechel

Simon M Petersen-Jones

Affiliations

Soon will be listed here.

Abstract

Purpose: The rdAc cat has an intronic mutation in the centrosomal 290 kDa (CEP290) gene resulting in a frameshift and a premature stop codon (c.6960 + 9 T > G, p.Ile2321AlafsTer3) predicted to truncate the protein by 157 amino acids. CEP290 mutations in human patients cause a range or phenotypes including syndromic conditions and severe childhood loss of vision while the rdAc cat has a milder phenotype. We sought to further characterize the effect of rdAc mutation on CEP290 expression.

Methods: TaqMan quantitative real-time polymerase chain reaction assays were used to compare wildtype and truncated transcript levels. Relative protein abundance was analyzed by Western blot. Immunohistochemistry (IHC) was performed to detect CEP290 protein.

Results: CEP290 mutant cats show low-level (17.4% of wildtype cats) use of the wildtype splice site and usage of the mutant splice site. Western analysis shows retina from cats homozygous for the mutation has CEP290 protein that likely comprises a combination of both wildtype and truncated protein. IHC detects CEP290 in affected and control retina labeling the region of the interconnecting cilium.

Conclusions: The comparably milder phenotype of CEP290 mutant cats is likely due to the retained production of some full-length CEP290 protein with possible functional contributions from presence of truncated protein.

Citing Articles

Cep131-Cep162 and Cby-Fam92 complexes cooperatively maintain Cep290 at the basal body and contribute to ciliogenesis initiation.

Wu Z, Chen H, Zhang Y, Wang Y, Wang Q, Augiere C PLoS Biol. 2024; 22(3):e3002330.

PMID: 38442096 PMC: 10914257. DOI: 10.1371/journal.pbio.3002330.

Alternative splicing in CEP290 mutant cats results in a milder phenotype than LCA patients.

Minella A, Narfstrom Wiechel K, Petersen-Jones S Vet Ophthalmol. 2022; 26(1):4-11.

PMID: 36495011 PMC: 10107307. DOI: 10.1111/vop.13052.

References

Narfstrom K, Nilsson S . Morphological findings during retinal development and maturation in hereditary rod-cone degeneration in Abyssinian cats. Exp Eye Res. 1989; 49(4):611-28. DOI: 10.1016/s0014-4835(89)80058-2. View

Minella A, Mowat F, Willett K, Sledge D, Bartoe J, Bennett J . Differential targeting of feline photoreceptors by recombinant adeno-associated viral vectors: implications for preclinical gene therapy trials. Gene Ther. 2014; 21(10):913-20. PMC: 4487421. DOI: 10.1038/gt.2014.65. View

Minella A, Narfstrom Wiechel K, Petersen-Jones S . Alternative splicing in CEP290 mutant cats results in a milder phenotype than LCA patients. Vet Ophthalmol. 2022; 26(1):4-11. PMC: 10107307. DOI: 10.1111/vop.13052. View

Helou J, Otto E, Attanasio M, Allen S, Parisi M, Glass I . Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior-Løken syndrome. J Med Genet. 2007; 44(10):657-63. PMC: 2597962. DOI: 10.1136/jmg.2007.052027. View

Anderson R, Maude M, Nilsson S, Narfstrom K . Plasma lipid abnormalities in the abyssinian cat with a hereditary rod-cone degeneration. Exp Eye Res. 1991; 53(3):415-7. DOI: 10.1016/0014-4835(91)90249-e. View

Seeliger M, Narfstrom K . Functional assessment of the regional distribution of disease in a cat model of hereditary retinal degeneration. Invest Ophthalmol Vis Sci. 2000; 41(7):1998-2005. View

Sayer J, Otto E, OToole J, Nurnberg G, Kennedy M, Becker C . The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet. 2006; 38(6):674-81. DOI: 10.1038/ng1786. View

Narfstrom K, Arden G, Nilsson S . Retinal sensitivity in hereditary retinal degeneration in Abyssinian cats: electrophysiological similarities between man and cat. Br J Ophthalmol. 1989; 73(7):516-21. PMC: 1041792. DOI: 10.1136/bjo.73.7.516. View

Padnick-Silver L, Kang Derwent J, Giuliano E, Narfstrom K, Linsenmeier R . Retinal oxygenation and oxygen metabolism in Abyssinian cats with a hereditary retinal degeneration. Invest Ophthalmol Vis Sci. 2006; 47(8):3683-9. DOI: 10.1167/iovs.05-1284. View

10.

Bainbridge J, Mehat M, Sundaram V, Robbie S, Barker S, Ripamonti C . Long-term effect of gene therapy on Leber's congenital amaurosis. N Engl J Med. 2015; 372(20):1887-97. PMC: 4497809. DOI: 10.1056/NEJMoa1414221. View

11.

Weleber R, Pennesi M, Wilson D, Kaushal S, Erker L, Jensen L . Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy. Ophthalmology. 2016; 123(7):1606-20. DOI: 10.1016/j.ophtha.2016.03.003. View

12.

Narfstrom K, Wilen M, Andersson B . Hereditary retinal degeneration in the Abyssinian cat: developmental studies using clinical electroretinography. Doc Ophthalmol. 1988; 69(2):111-8. DOI: 10.1007/BF00153691. View

13.

Narfstrom K . Hereditary progressive retinal atrophy in the Abyssinian cat. J Hered. 1983; 74(4):273-6. DOI: 10.1093/oxfordjournals.jhered.a109782. View

14.

Garanto A, Chung D, Duijkers L, Corral-Serrano J, Messchaert M, Xiao R . In vitro and in vivo rescue of aberrant splicing in CEP290-associated LCA by antisense oligonucleotide delivery. Hum Mol Genet. 2016; 25(12):2552-2563. PMC: 6086559. DOI: 10.1093/hmg/ddw118. View

15.

den Hollander A, Koenekoop R, Yzer S, Lopez I, Arends M, Voesenek K . Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet. 2006; 79(3):556-61. PMC: 1559533. DOI: 10.1086/507318. View

16.

Narfstrom K, Ehinger B, Bruun A . Immunohistochemical studies of cone photoreceptors and cells of the inner retina in feline rod-cone degeneration. Vet Ophthalmol. 2001; 4(2):141-5. DOI: 10.1046/j.1463-5224.2001.00191.x. View

17.

Ghazi N, Abboud E, Nowilaty S, Alkuraya H, Alhommadi A, Cai H . Treatment of retinitis pigmentosa due to MERTK mutations by ocular subretinal injection of adeno-associated virus gene vector: results of a phase I trial. Hum Genet. 2016; 135(3):327-43. DOI: 10.1007/s00439-016-1637-y. View

18.

May C, Narfstrom K . Choroidal microcirculation in Abyssinian cats with hereditary rod-cone degeneration. Exp Eye Res. 2008; 86(3):537-40. DOI: 10.1016/j.exer.2007.12.011. View

19.

Tory K, Lacoste T, Burglen L, Moriniere V, Boddaert N, Macher M . High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations. J Am Soc Nephrol. 2007; 18(5):1566-75. DOI: 10.1681/ASN.2006101164. View

20.

Narfstrom K . Progressive retinal atrophy in the Abyssinian cat. Clinical characteristics. Invest Ophthalmol Vis Sci. 1985; 26(2):193-200. View