CNGA3
Cyclic nucleotide-gated cation channel alpha-3 (Cone photoreceptor cGMP-gated channel subunit alpha) (Cyclic nucleotide-gated channel alpha-3) (CNG channel alpha-3) (CNG-3) (CNG3) [CNCG3]
Publications[править]
DNA methylation is currently one of the most promising age-predictive biomarkers. Many studies have reported DNA methylation-based age predictive models, but most of these are based on DNA methylation patterns from blood. Only a few studies have examined age-predictive DNA patterns in saliva, which is one of the most frequently-encountered body fluids at crime scenes. In this study, we generated genome-wide DNA methylation profiles of saliva from 54 individuals and identified CpG markers that showed a high correlation between methylation and age. Because the age-associated marker candidates from saliva differed from those of blood, we investigated DNA methylation patterns of 6 age-associated CpG marker candidates (cg00481951, cg19671120, cg14361627, cg08928145, cg12757011, and cg07547549 of the SST, CNGA3, KLF14, TSSK6, TBR1, and SLC12A5 genes, respectively) in addition to a cell type-specific CpG marker (cg18384097 of the PTPN7 gene) in an independent set of saliva samples obtained from 226 individuals aged 18 to 65 years. Multiplex methylation SNaPshot reactions were used to generate the data. We then generated a linear regression model with age information and the methylation profile from the 113 training samples. The model exhibited a 94.5% correlation between predicted and chronological age with a mean absolute deviation (MAD) from chronological age of 3.13 years. In subsequent validation using 113 test samples, we also observed a high correlation between predicted and chronological age (Spearman's rho=0.952, MAD from chronological age=3.15years). The model composed of 7 selected CpG sites enabled age prediction in saliva with high accuracy, which will be useful in saliva analysis for investigative leads.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- CpG Islands
- DNA Methylation
- Forensic Genetics
- Genetic Markers
- Humans
- Linear Models
- Middle Aged
- Nucleic Acid Hybridization
- Saliva
- Young Adult
Keywords
- Age
- DNA methylation
- HumanMethylation450 BeadChip
- SNaPshot
- Saliva
Mutations in the CNGB3 gene account for >50% of all known cases of achromatopsia. Although of early onset, its stationary character and the potential for rapid assessment of restoration of retinal function following therapy renders achromatopsia a very attractive candidate for gene therapy. Here we tested the efficacy of an rAAV2/8 vector containing a human cone arrestin promoter and a human CNGB3 cDNA in CNGB3 deficient mice. Following subretinal delivery of the vector, CNGB3 was detected in both M- and S-cones and resulted in increased levels of CNGA3, increased cone density and survival, improved cone outer segment structure and normal subcellular compartmentalization of cone opsins. Therapy also resulted in long-term improvement of retinal function, with restoration of cone ERG amplitudes of up to 90% of wild-type and a significant improvement in visual acuity. Remarkably, successful restoration of cone function was observed even when treatment was initiated at 6 months of age; however, restoration of normal visual acuity was only possible in younger animals (e.g. 2-4 weeks old). This study represents achievement of the most substantial restoration of visual function reported to date in an animal model of achromatopsia using a human gene construct, which has the potential to be utilized in clinical trials.
MeSH Terms
- Aging
- Animals
- Arrestins
- Cell Survival
- Color Vision Defects
- Cyclic Nucleotide-Gated Cation Channels
- Disease Models, Animal
- Gene Transfer Techniques
- Genetic Therapy
- Genetic Vectors
- Humans
- Injections
- Mice
- Mice, Transgenic
- Opsins
- Organ Specificity
- Promoter Regions, Genetic
- Protein Transport
- Retina
- Retinal Cone Photoreceptor Cells
- Time Factors
- Vision, Ocular
- Visual Acuity