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Whole-exome sequencing identified ARL2 as a novel candidate gene for MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome.
Clin Genet 2019; 96(1):61-71CG

Abstract

Adenosine diphosphate (ADP)-ribosylation factor-like 2 (ARL2) protein participates in a broad range of cellular processes and acts as a mediator for mutant ARL2BP in cilium-associated retinitis pigmentosa and for mutant HRG4 in mitochondria-related photoreceptor degeneration. However, mutant ARL2 has not been linked to any human disease so far. Here, we identified a de novo variant in ARL2 (c.44G > T, p.R15L) in a Chinese pedigree with MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome through whole-exome sequencing and co-segregation analysis. Co-immunoprecipitation assay and immunoblotting confirmed that the mutant ARL2 protein showed a 62% lower binding affinity for HRG4 while a merely 18% lower binding affinity for ARL2BP. Immunofluorescence images of ARL2 and HRG4 co-localizing with cytochrome c in HeLa cells described their relationship with mitochondria. Further analyses of the mitochondrial respiratory chain and adenosine triphosphate production showed significant abnormalities under an ARL2-mutant condition. Finally, we generated transgenic mice to test the pathogenicity of this variant and observed retinal degeneration complicated with microcornea and cataract that were similar to those in our patients. In conclusion, we uncover ARL2 as a novel candidate gene for MRCS syndrome and suggest a mitochondria-related mechanism of the first ARL2 variant through site-directed mutagenesis studies.

Authors+Show Affiliations

Lab for Stem Cell and Retinal Regeneration, Institute of Stem Cell Research; Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China. State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.Lab for Stem Cell and Retinal Regeneration, Institute of Stem Cell Research; Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China. State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.Lab for Stem Cell and Retinal Regeneration, Institute of Stem Cell Research; Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China. State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.Lab for Stem Cell and Retinal Regeneration, Institute of Stem Cell Research; Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China. State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.Lab for Stem Cell and Retinal Regeneration, Institute of Stem Cell Research; Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China. State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.Lab for Stem Cell and Retinal Regeneration, Institute of Stem Cell Research; Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China. State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.Lab for Stem Cell and Retinal Regeneration, Institute of Stem Cell Research; Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China. State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.Lab for Stem Cell and Retinal Regeneration, Institute of Stem Cell Research; Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China. State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.Protein Quality Control and Diseases Laboratory, Institute of Biophysics, School of Life Sciences, Wenzhou Medical University, Wenzhou, China.State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.Lab for Stem Cell and Retinal Regeneration, Institute of Stem Cell Research; Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China. State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30945270

Citation

Cai, Xue-Bi, et al. "Whole-exome Sequencing Identified ARL2 as a Novel Candidate Gene for MRCS (microcornea, Rod-cone Dystrophy, Cataract, and Posterior Staphyloma) Syndrome." Clinical Genetics, vol. 96, no. 1, 2019, pp. 61-71.
Cai XB, Wu KC, Zhang X, et al. Whole-exome sequencing identified ARL2 as a novel candidate gene for MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome. Clin Genet. 2019;96(1):61-71.
Cai, X. B., Wu, K. C., Zhang, X., Lv, J. N., Jin, G. H., Xiang, L., ... Jin, Z. B. (2019). Whole-exome sequencing identified ARL2 as a novel candidate gene for MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome. Clinical Genetics, 96(1), pp. 61-71. doi:10.1111/cge.13541.
Cai XB, et al. Whole-exome Sequencing Identified ARL2 as a Novel Candidate Gene for MRCS (microcornea, Rod-cone Dystrophy, Cataract, and Posterior Staphyloma) Syndrome. Clin Genet. 2019;96(1):61-71. PubMed PMID: 30945270.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Whole-exome sequencing identified ARL2 as a novel candidate gene for MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome. AU - Cai,Xue-Bi, AU - Wu,Kun-Chao, AU - Zhang,Xiao, AU - Lv,Ji-Neng, AU - Jin,Guang-Hui, AU - Xiang,Lue, AU - Chen,Jie, AU - Huang,Xiu-Feng, AU - Pan,Deng, AU - Lu,Bin, AU - Lu,Fan, AU - Qu,Jia, AU - Jin,Zi-Bing, Y1 - 2019/04/22/ PY - 2018/11/19/received PY - 2019/03/20/revised PY - 2019/03/21/accepted PY - 2019/4/5/pubmed PY - 2019/4/5/medline PY - 2019/4/5/entrez KW - ARL2 KW - MRCS syndrome KW - de novo variant KW - mitochondria SP - 61 EP - 71 JF - Clinical genetics JO - Clin. Genet. VL - 96 IS - 1 N2 - Adenosine diphosphate (ADP)-ribosylation factor-like 2 (ARL2) protein participates in a broad range of cellular processes and acts as a mediator for mutant ARL2BP in cilium-associated retinitis pigmentosa and for mutant HRG4 in mitochondria-related photoreceptor degeneration. However, mutant ARL2 has not been linked to any human disease so far. Here, we identified a de novo variant in ARL2 (c.44G > T, p.R15L) in a Chinese pedigree with MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome through whole-exome sequencing and co-segregation analysis. Co-immunoprecipitation assay and immunoblotting confirmed that the mutant ARL2 protein showed a 62% lower binding affinity for HRG4 while a merely 18% lower binding affinity for ARL2BP. Immunofluorescence images of ARL2 and HRG4 co-localizing with cytochrome c in HeLa cells described their relationship with mitochondria. Further analyses of the mitochondrial respiratory chain and adenosine triphosphate production showed significant abnormalities under an ARL2-mutant condition. Finally, we generated transgenic mice to test the pathogenicity of this variant and observed retinal degeneration complicated with microcornea and cataract that were similar to those in our patients. In conclusion, we uncover ARL2 as a novel candidate gene for MRCS syndrome and suggest a mitochondria-related mechanism of the first ARL2 variant through site-directed mutagenesis studies. SN - 1399-0004 UR - https://www.unboundmedicine.com/medline/citation/30945270/Whole-exome_sequencing_identified_ARL2_as_a_novel_candidate_gene_for_MRCS_(microcornea,_rod-cone_dystrophy,_cataract,_and_posterior_staphyloma)_syndrome L2 - https://doi.org/10.1111/cge.13541 DB - PRIME DP - Unbound Medicine ER -