Journal
CLINICAL GENETICS
Volume 96, Issue 1, Pages 61-71Publisher
WILEY
DOI: 10.1111/cge.13541
Keywords
ARL2; de novo variant; mitochondria; MRCS syndrome
Categories
Funding
- Ministry of Education 111 project [D16011]
- National Natural Science Foundation of China [81522014, 31771390]
- Natural Science Foundation of Zhejiang Province [LD18H120001LD]
- Wenzhou Science and Technology Innovation Team Project [C20150004]
- Zhejiang Provincial Key Research and Development Program [2015C03029]
- National Key Research and Development Program of China [2017YFA0105300]
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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.
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