Mutation of <i>CRYAB</i> encoding a conserved mitochondrial chaperone and anti-apoptotic protein causes hereditary optic atrophy

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

doi:10.1172/jci.insight.182209

Mutation of CRYAB encoding a conserved mitochondrial chaperone and anti-apoptotic protein causes hereditary optic atrophy

Chenghui Wang,¹ Liyao Zhang,² Zhipeng Nie,² Min Liang,³ Hanqing Liu,² Qiuzi Yi,² Chunyan Wang,² Cheng Ai,² Juanjuan Zhang,³ Yinglong Gao,⁴ Yanchun Ji,⁴ and Min-Xin Guan¹

Published November 19, 2024 - More info

View PDF

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 novel optic atrophy-causative CRYAB gene encoding a highly conserved major lens protein acting as mitochondrial chaperone and possessing anti-apoptotic 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 decreasing chaperone activity. Coimmunoprecipitation indicated that the p.E105K mutation reduced the interaction of CRYAB with apoptosis-associated cytochrome c and VDAC. The cell lines carrying the p.E105K mutation displayed promoting apoptosis, defective assembly, stability and activities of oxidative phosphorylation system and imbalance of mitochondrial dynamics. Involvement of CRYAB in optic atrophy was confirmed by phenotypic evaluations of Cryab^p.E105K knock-in mice. These mutant mice exhibited ocular lesions including changing intra-retina layers, degeneration of RGCs, photoreceptor deficits and abnormal retinal vasculature. Furthermore, Cryab-deficient mice displayed elevated apoptosis and mitochondrial dysfunctions. Our findings provide new insight of pathophysiology of optic atrophy arising from RGC degeneration caused by CRYAB deficiency-induced elevated apoptosis and mitochondrial dysfunctions.

Mutation of CRYAB encoding a conserved mitochondrial chaperone and anti-apoptotic protein causes hereditary optic atrophy

Chenghui Wang,¹ Liyao Zhang,² Zhipeng Nie,² Min Liang,³ Hanqing Liu,² Qiuzi Yi,² Chunyan Wang,² Cheng Ai,² Juanjuan Zhang,³ Yinglong Gao,⁴ Yanchun Ji,⁴ and Min-Xin Guan¹

Article tools

Metrics

Go to

Mutation of CRYAB encoding a conserved mitochondrial chaperone and anti-apoptotic protein causes hereditary optic atrophy

Chenghui Wang,1 Liyao Zhang,2 Zhipeng Nie,2 Min Liang,3 Hanqing Liu,2 Qiuzi Yi,2 Chunyan Wang,2 Cheng Ai,2 Juanjuan Zhang,3 Yinglong Gao,4 Yanchun Ji,4 and Min-Xin Guan1

Article tools

Metrics

Go to

Sign up for email alerts

Chenghui Wang,¹ Liyao Zhang,² Zhipeng Nie,² Min Liang,³ Hanqing Liu,² Qiuzi Yi,² Chunyan Wang,² Cheng Ai,² Juanjuan Zhang,³ Yinglong Gao,⁴ Yanchun Ji,⁴ and Min-Xin Guan¹