Mutation of CRYAB Encoding a Conserved Mitochondrial Chaperone and Antiapoptotic Protein Causes Hereditary Optic Atrophy

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2024 Nov 19

PMID 39561005

Authors

Chenghui Wang

Liyao Zhang

Zhipeng Nie

Min Liang

Hanqing Liu

Qiuzi Yi

Chunyan Wang

Cheng Ai

Juanjuan Zhang

Yinglong Gao

Yanchun Ji

Min-Xin Guan

Affiliations

Soon will be listed here.

Abstract

The degeneration of retinal ganglion cells (RGC) due to mitochondrial dysfunctions manifests optic neuropathy. However, the molecular components of RGC linked to optic neuropathy manifestations remain largely unknown. Here, we identified a potentially novel optic atrophy-causative CRYAB gene encoding a highly conserved major lens protein acting as mitochondrial chaperone and possessing antiapoptotic activities. The heterozygous CRYAB mutation (c.313G>A, p. Glu105Lys) was cosegregated with autosomal dominant inheritance of optic atrophy in 3 Chinese families. The p.E105K mutation altered the structure and function of CRYAB, including decreased stability, reduced formation of oligomers, and decreased chaperone activity. Coimmunoprecipitation indicated that the p.E105K mutation reduced the interaction of CRYAB with apoptosis-associated cytochrome c and voltage-dependent anion channel protein. The cell lines carrying the p.E105K mutation displayed promotion of apoptosis and defective assembly, stability, and activities of oxidative phosphorylation system as well as imbalance of mitochondrial dynamics. Involvement of CRYAB in optic atrophy was confirmed by phenotypic evaluations of Cryabp.E105K-knockin mice. These mutant mice exhibited ocular lesions that included alteration of intraretinal layers, degeneration of RGCs, photoreceptor deficits, and abnormal retinal vasculature. Furthermore, Cryab-deficient mice displayed elevated apoptosis and mitochondrial dysfunctions. Our findings provide insight of pathophysiology of optic atrophy arising from RGC degeneration caused by CRYAB deficiency-induced elevated apoptosis and mitochondrial dysfunctions.

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