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, Sheikh Amer Riazuddin, Radha Ayyagari, Shaikh Riazuddin

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2483-2497
Number of pages15
JournalHuman Molecular Genetics
Volume25
Issue number12
StatePublished - Jun 15 2016
Externally publishedYes

Fingerprint

Asparaginase
Retinal Degeneration
Missense Mutation
Retinal Dystrophies
Mutation
Genes
Pedigree
Exome
Retinal Cone Photoreceptor Cells
Protein Precursors
Asparagine
Zebrafish
Enzymes
Hydrolysis
Escherichia coli
Phenotype
Peptides
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Biswas, P., Chavali, V. R. M., Agnello, G., Stone, E., Chakarova, C., Duncan, J. L., ... Riazuddin, S. (2016). A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration. Human Molecular Genetics, 25(12), 2483-2497.

A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration. / Biswas, Pooja; Chavali, Venkata Ramana Murthy; Agnello, Giulia; Stone, Everett; Chakarova, Christina; Duncan, Jacque L.; Kannabiran, Chitra; Homsher, Melissa; Bhattacharya, Shomi S.; Naeem, Muhammad Asif; Kimchi, Adva; Sharon, Dror; Iwata, Takeshi; Riazuddin, Shaikh; Reddy, G. Bhanuprakash; Hejtmancik, J. Fielding; Georgiou, George; Riazuddin, Sheikh Amer; Ayyagari, Radha; Riazuddin, Shaikh.

In: Human Molecular Genetics, Vol. 25, No. 12, 15.06.2016, p. 2483-2497.

Research output: Contribution to journalArticle

Biswas, P, Chavali, VRM, Agnello, G, Stone, E, Chakarova, C, Duncan, JL, Kannabiran, C, Homsher, M, Bhattacharya, SS, Naeem, MA, Kimchi, A, Sharon, D, Iwata, T, Riazuddin, S, Reddy, GB, Hejtmancik, JF, Georgiou, G, Riazuddin, SA, Ayyagari, R & Riazuddin, S 2016, 'A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration', Human Molecular Genetics, vol. 25, no. 12, pp. 2483-2497.
Biswas P, Chavali VRM, Agnello G, Stone E, Chakarova C, Duncan JL et al. A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration. Human Molecular Genetics. 2016 Jun 15;25(12):2483-2497.
Biswas, Pooja ; Chavali, Venkata Ramana Murthy ; Agnello, Giulia ; Stone, Everett ; Chakarova, Christina ; Duncan, Jacque L. ; Kannabiran, Chitra ; Homsher, Melissa ; Bhattacharya, Shomi S. ; Naeem, Muhammad Asif ; Kimchi, Adva ; Sharon, Dror ; Iwata, Takeshi ; Riazuddin, Shaikh ; Reddy, G. Bhanuprakash ; Hejtmancik, J. Fielding ; Georgiou, George ; Riazuddin, Sheikh Amer ; Ayyagari, Radha ; Riazuddin, Shaikh. / A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 12. pp. 2483-2497.
@article{e03207f3662a4cf7acb0e2e1a96266ef,
title = "A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration",
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.",
author = "Pooja Biswas and Chavali, {Venkata Ramana Murthy} and Giulia Agnello and Everett Stone and Christina Chakarova and Duncan, {Jacque L.} and Chitra Kannabiran and Melissa Homsher and Bhattacharya, {Shomi S.} and Naeem, {Muhammad Asif} and Adva Kimchi and Dror Sharon and Takeshi Iwata and Shaikh Riazuddin and Reddy, {G. Bhanuprakash} and Hejtmancik, {J. Fielding} and George Georgiou and Riazuddin, {Sheikh Amer} and Radha Ayyagari and Shaikh Riazuddin",
year = "2016",
month = "6",
day = "15",
language = "English (US)",
volume = "25",
pages = "2483--2497",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "12",

}

TY - JOUR

T1 - A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration

AU - Biswas, Pooja

AU - Chavali, Venkata Ramana Murthy

AU - Agnello, Giulia

AU - Stone, Everett

AU - Chakarova, Christina

AU - Duncan, Jacque L.

AU - Kannabiran, Chitra

AU - Homsher, Melissa

AU - Bhattacharya, Shomi S.

AU - Naeem, Muhammad Asif

AU - Kimchi, Adva

AU - Sharon, Dror

AU - Iwata, Takeshi

AU - Riazuddin, Shaikh

AU - Reddy, G. Bhanuprakash

AU - Hejtmancik, J. Fielding

AU - Georgiou, George

AU - Riazuddin, Sheikh Amer

AU - Ayyagari, Radha

AU - Riazuddin, Shaikh

PY - 2016/6/15

Y1 - 2016/6/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84988351690&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84988351690&partnerID=8YFLogxK

M3 - Article

VL - 25

SP - 2483

EP - 2497

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 12

ER -