Whole-exome sequencing identified ARL2 as a novel candidate gene for MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome.
Xue-Bi CaiKun-Chao WuXiao ZhangJi-Neng LvGuang-Hui JinLue XiangJie ChenXiu-Feng HuangDeng PanBin LuFan LuJia QuZi-Bing JinPublished in: Clinical genetics (2019)
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.
Keyphrases
- end stage renal disease
- cell death
- chronic kidney disease
- early onset
- ejection fraction
- induced apoptosis
- case report
- endothelial cells
- crispr cas
- peritoneal dialysis
- genome wide
- mass spectrometry
- machine learning
- small molecule
- gene expression
- endoplasmic reticulum
- signaling pathway
- transcription factor
- convolutional neural network
- amino acid
- endoplasmic reticulum stress
- cell proliferation
- patient reported outcomes
- biofilm formation
- dna binding
- respiratory tract