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

Pooja Biswas, Venkata Ramana Murthy Chavali, Giulia Agnello, Everett Stone, Christina Chakarova, Jacque L. Duncan, Chitra Kannabiran, Melissa Homsher, Shomi S. Bhattacharya, Muhammad Asif Naeem, Adva Kimchi, Dror Sharon, Takeshi Iwata, Shaikh Riazuddin, G. Bhanuprakash Reddy, J. Fielding Hejtmancik, George Georgiou, S. Amer Riazuddin, Radha Ayyagari, Shaikh Riazuddin

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2483-2497
Number of pages15
JournalHuman molecular genetics
Issue number12
StatePublished - Jun 15 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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