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已发表论文
亚洲家系中索斯比眼底营养不良：致病性 Timp3 P.Y191c 变异影响其与 Mmp2/9 的结合及细胞定位
Authors Li M, Peng H, Ding S, Wei Y, Zhang L, Zhou Z, Tang H, Shi P, Liang Y, Li G, Tao Y, Song Z
Received 27 July 2025
Accepted for publication 1 December 2025
Published 9 December 2025 Volume 2025:19 Pages 4551—4564
DOI https://doi.org/10.2147/OPTH.S556592
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Yousef Fouad
Miao Li,1 Haiying Peng,1 Shenao Ding,1 Yuanmeng Wei,1 Leying Zhang,1 Zhongqiang Zhou,1 He Tang,1 Pingling Shi,1 Yingjuan Liang,1 Guanfeng Li,2 Ye Tao,1 Zongming Song1
1Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan, People’s Hospital, Zhengzhou, People’s Republic of China; 2Department of Ophthalmology, Henan Children’s Hospital, Zhengzhou, People’s Republic of China
Correspondence: Zhongqiang Zhou, Email zhouzhongqiang110@163.com Zongming Song, Email smeyes@zzu.edu.cn
Purpose: To characterize the clinical phenotype and elucidate the pathogenic mechanism of the novel TIMP3 p.Y191C variant in a multigenerational Asian pedigree with Sorsby Fundus Dystrophy (SFD).
Methods: Affected family members underwent comprehensive ophthalmic evaluations. Genetic analysis was performed via whole-exome and Sanger sequencing. An ARPE-19 cell models overexpressing wild-type or mutant TIMP3 were generated. Functional analysis including co-immunoprecipitation (Co-IP), MMP inhibition, and immunofluorescence were performed.
Results: A heterozygous TIMP3 p.Y191C variant was identified in seven affected members, co-segregating with bilateral choroidal neovascularization and disciform scarring. The tyrosine-191 residue is highly conserved, and structural/computational analyses predicted that the cysteine substitution introduces a smaller, hydrophobic residue and reduces protein stability. Functionally, the Y191C variant impaired TIMP3 binding to MMP2 and MMP9, reduced its inhibitory activity, and altered MMP2 localization following LPS stimulation. Consistent with this loss of function, the mutant TIMP3 significantly inhibited cell viability and promoted apoptosis in ARPE-19 cells under inflammatory stress.
Conclusion: The novel TIMP3 p.Y191C variant causes SFD in an Asian pedigree. Its pathogenicity arises from distinct disruptions in MMP2/9 binding and inhibition, coupled with altered MMP2 localization, thereby providing a mechanistic basis for the disease.
Keywords: sorsby fundus dystrophy, pathogenic variant, TIMP3, MMP2, MMP9
1Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan, People’s Hospital, Zhengzhou, People’s Republic of China; 2Department of Ophthalmology, Henan Children’s Hospital, Zhengzhou, People’s Republic of China
Correspondence: Zhongqiang Zhou, Email zhouzhongqiang110@163.com Zongming Song, Email smeyes@zzu.edu.cn
Purpose: To characterize the clinical phenotype and elucidate the pathogenic mechanism of the novel TIMP3 p.Y191C variant in a multigenerational Asian pedigree with Sorsby Fundus Dystrophy (SFD).
Methods: Affected family members underwent comprehensive ophthalmic evaluations. Genetic analysis was performed via whole-exome and Sanger sequencing. An ARPE-19 cell models overexpressing wild-type or mutant TIMP3 were generated. Functional analysis including co-immunoprecipitation (Co-IP), MMP inhibition, and immunofluorescence were performed.
Results: A heterozygous TIMP3 p.Y191C variant was identified in seven affected members, co-segregating with bilateral choroidal neovascularization and disciform scarring. The tyrosine-191 residue is highly conserved, and structural/computational analyses predicted that the cysteine substitution introduces a smaller, hydrophobic residue and reduces protein stability. Functionally, the Y191C variant impaired TIMP3 binding to MMP2 and MMP9, reduced its inhibitory activity, and altered MMP2 localization following LPS stimulation. Consistent with this loss of function, the mutant TIMP3 significantly inhibited cell viability and promoted apoptosis in ARPE-19 cells under inflammatory stress.
Conclusion: The novel TIMP3 p.Y191C variant causes SFD in an Asian pedigree. Its pathogenicity arises from distinct disruptions in MMP2/9 binding and inhibition, coupled with altered MMP2 localization, thereby providing a mechanistic basis for the disease.
Keywords: sorsby fundus dystrophy, pathogenic variant, TIMP3, MMP2, MMP9