Exome-wide association study identifies KDELR3 mutations in extreme myopia

Jian Yuan, You-Yuan Zhuang, Xiaoyu Liu, Yue Zhang, Kai Li, Zhen Ji Chen, Dandan Li, He Chen, Jiacheng Liang, Yinghao Yao, Xiangyi Yu, Ran Zhuo, Fei Zhao, Xiangtian Zhou, Xiaoguang Yu (), Jia Qu () and Jianzhong Su ()
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Jian Yuan: Wenzhou Medical University
You-Yuan Zhuang: Wenzhou Medical University
Xiaoyu Liu: Wenzhou Medical University
Yue Zhang: Wenzhou Medical University
Kai Li: University of Chinese Academy of Sciences
Zhen Ji Chen: Wenzhou Medical University
Dandan Li: Wenzhou Medical University
He Chen: Hainan University
Jiacheng Liang: Wenzhou Medical University
Yinghao Yao: Vision and Brain Health
Xiangyi Yu: Institute of PSI Genomics
Ran Zhuo: Wenzhou Medical University
Fei Zhao: Wenzhou Medical University
Xiangtian Zhou: Wenzhou Medical University
Xiaoguang Yu: Institute of PSI Genomics
Jia Qu: Wenzhou Medical University
Jianzhong Su: Wenzhou Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Extreme myopia (EM), defined as a spherical equivalent (SE) ≤ −10.00 diopters (D), is one of the leading causes of sight impairment. Known EM-associated variants only explain limited risk and are inadequate for clinical decision-making. To discover risk genes, we performed a whole-exome sequencing (WES) on 449 EM individuals and 9606 controls. We find a significant excess of rare protein-truncating variants (PTVs) in EM cases, enriched in the retrograde vesicle-mediated transport pathway. Employing single-cell RNA-sequencing (scRNA-seq) and a single-cell polygenic burden score (scPBS), we pinpointed PI16 + /SFRP4+ fibroblasts as the most relevant cell type. We observed that KDELR3 is highly expressed in scleral fibroblast and involved in scleral extracellular matrix (ECM) organization. The zebrafish model revealed that kdelr3 downregulation leads to elongated ocular axial length and increased lens diameter. Together, our study provides insight into the genetics of EM in humans and highlights KDELR3’s role in EM pathogenesis.

Date: 2024
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DOI: 10.1038/s41467-024-50580-x

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