A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration

Hum Mol Genet. 2016 Jun 15;25(12):2483-2497. doi: 10.1093/hmg/ddw113.

Pooja Biswas ¹, Venkata Ramana Murthy Chavali ² ², Giulia Agnello ³, Everett Stone ³, Christina Chakarova ⁴, Jacque L Duncan ⁵, Chitra Kannabiran ⁶, Melissa Homsher ², Shomi S Bhattacharya ⁴, Muhammad Asif Naeem ⁷, Adva Kimchi ⁸, Dror Sharon ⁸, Takeshi Iwata ⁹, Shaikh Riazuddin ¹⁰ ¹¹, G Bhanuprakash Reddy ¹², J Fielding Hejtmancik ¹³, George Georgiou ³, S Amer Riazuddin ¹⁴, Radha Ayyagari ¹⁵

Affiliations

1 Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA.
2 Ophthalmology, University of Pennsylvania, Philadelphia, PA, USA.
3 Departments of Biomedical and Chemical Engineering, Molecular Biosciences, Section of Molecular Genetics and Microbiology, and Institute for Cell and Molecular Biology, The University of Texas at Austin, Austin, TX, USA.
4 UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
5 Ophthalmology, University of California San Francisco, San Francisco, CA, USA.
6 Kallam Anji Reddy Molecular Genetics Laboratory, L V Prasad Eye Institute (LVPEI), Kallam Anji Reddy Campus, L V Prasad Marg, Hyderabad 500 034, India.
7 National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
8 Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
9 Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
10 Allama Iqbal Medical College, University of Health Sciences Lahore, Pakistan.
11 National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
12 National Institute of Nutrition, Hyderabad 500 007, India.
13 OMGS/OGVFB branch, National Eye Institute, NIH, Bethesda, MD, USA.
14 The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA [email protected] [email protected].
15 Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA [email protected] [email protected].

PMID: 27106100 DOI: 10.1093/hmg/ddw113

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 the retinal dystrophy phenotype in the study pedigree. ASRGL1 encodes an Enzyme that catalyzes the hydrolysis of L-asparagine and isoaspartyl-peptides. Studies on the ASRGL1 expressed in Escherichia 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 hASRGL1 developed 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.

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