A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration.
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.
Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA.
Pooja
P
Biswas
Ophthalmology, University of Pennsylvania, Philadelphia, PA, USA.|Ophthalmology, University of Pennsylvania, Philadelphia, PA, USA.
Venkata Ramana Murthy
VR
Chavali
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.
Giulia
G
Agnello
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.
Everett
E
Stone
UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
Christina
C
Chakarova
Ophthalmology, University of California San Francisco, San Francisco, CA, USA.
Jacque L
JL
Duncan
Kallam Anji Reddy Molecular Genetics Laboratory, L V Prasad Eye Institute (LVPEI), Kallam Anji Reddy Campus, L V Prasad Marg, Hyderabad 500 034, India.
Chitra
C
Kannabiran
Ophthalmology, University of Pennsylvania, Philadelphia, PA, USA.
Melissa
M
Homsher
UCL Institute of Ophthalmology, 11-43 Bath Street, London, UK.
Shomi S
SS
Bhattacharya
National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
Muhammad Asif
MA
Naeem
Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Adva
A
Kimchi
Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Dror
D
Sharon
Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
Takeshi
T
Iwata
Allama Iqbal Medical College, University of Health Sciences Lahore, Pakistan.|National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
Shaikh
S
Riazuddin
National Institute of Nutrition, Hyderabad 500 007, India.
G Bhanuprakash
GB
Reddy
OMGS/OGVFB branch, National Eye Institute, NIH, Bethesda, MD, USA.
J Fielding
JF
Hejtmancik
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.
George
G
Georgiou
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA rayyagari@ucsd.edu riazuddin@jhmi.edu.
S Amer
SA
Riazuddin
Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA rayyagari@ucsd.edu riazuddin@jhmi.edu.
Radha
R
Ayyagari
D000328:Adult; D000818:Animals; D001215:Asparaginase / Q000235:genetics*; D001324:Autoantigens / Q000235:genetics*; D004195:Disease Models, Animal; D059472:Exome / Q000235:genetics; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000473:pathology*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D014792:Visual Acuity / Q000235:genetics / Q000502:physiology; D015027:Zebrafish / Q000235:genetics
D001324:Autoantigens; C466840:ASRGL1 protein, human; D001215:Asparaginase