PUBLICATION
A missense mutation in the ASRGL1 gene is involved in causing autosomal recessive retinal degeneration
- Authors
- Biswas, P., Chavali, V.R., Agnello, G., Stone, E., Chakarova, C., Duncan, J.L., Kannabiran, C., Homsher, M., Bhattacharya, S.S., Naeem, M.A., Kimchi, A., Sharon, D., Iwata, T., Riazuddin, S., Reddy, G.B., Hejtmancik, J.F., Gerogiou, G., Riazuddin, S.A., Ayyagari, R.
- ID
- ZDB-PUB-160424-7
- Date
- 2016
- Source
- Human molecular genetics 25(12): 2483-2497 (Journal)
- Registered Authors
- Hejtmancik, J. Fielding
- Keywords
- none
- MeSH Terms
-
- Humans
- Genetic Predisposition to Disease*
- Asparaginase/genetics*
- Pedigree
- Animals
- Male
- Visual Acuity/genetics
- Visual Acuity/physiology
- Middle Aged
- Disease Models, Animal
- Exome/genetics
- Retinal Cone Photoreceptor Cells/metabolism
- Retinal Cone Photoreceptor Cells/pathology*
- Mutation, Missense
- Autoantigens/genetics*
- Retina/pathology*
- Phenotype
- Genetic Linkage
- Zebrafish/genetics
- Adult
- Retinal Degeneration/genetics*
- Retinal Degeneration/pathology
- PubMed
- 27106100 Full text @ Hum. Mol. Genet.
Citation
Biswas, P., Chavali, V.R., Agnello, G., Stone, E., Chakarova, C., Duncan, J.L., Kannabiran, C., Homsher, M., Bhattacharya, S.S., Naeem, M.A., Kimchi, A., Sharon, D., Iwata, T., Riazuddin, S., Reddy, G.B., Hejtmancik, J.F., Gerogiou, G., Riazuddin, S.A., Ayyagari, R. (2016) A missense mutation in the ASRGL1 gene is involved in causing autosomal recessive retinal degeneration. Human molecular genetics. 25(12):2483-2497.
Abstract
Inherited retinal dystrophies are a group of genetically heterogeneous conditions with broad phenotypic heterogeneity. We analyzed a large five-generation pedigree with early-onset recessive retinal degeneration to identify the causative mutation. Linkage analysis and homozygosity mapping combined with exome sequencing were carried out to map the disease locus and identify the p.G178R mutation in the Asparaginase-like 1 gene (ASRGL1), segregating with retinal dystrophy phenotype in the study pedigree. The ASRGL1 gene encodes an enzyme that catalyzes the hydrolysis of L-asparagine and isoaspartyl-dipeptides. Studies on the ASRGL1 expressed in E. coli and transiently transfected mammalian cells indicated that the p.G178R mutation impairs the autocatalytic processing of this enzyme resulting in the loss of functional ASRGL1 and leaving the inactive precursor protein as a destabilized and aggregation-prone protein. A zebrafish model overexpressing the mutant hASRGL1developed retinal abnormalities and loss of cone photoreceptors. Our studies suggest that the p.G178R mutation in ASRGL1 leads to photoreceptor degeneration resulting in progressive vision loss.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping