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Exome-wide association study identifies KDELR3 mutations in extreme myopia.

Jian YuanYou-Yuan ZhuangXiaoyu LiuYue ZhangKai LiZhen Ji ChenDandan LiHe ChenJiacheng LiangYinghao YaoXiangyi YuRan ZhuoFei ZhaoXiangtian Zhounull nullXiaoguang YuJia QuJianzhong Su
Published in: Nature communications (2024)
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.
Keyphrases
  • single cell
  • extracellular matrix
  • rna seq
  • genome wide
  • copy number
  • high throughput
  • decision making
  • climate change
  • optic nerve
  • cell proliferation
  • signaling pathway
  • transcription factor
  • protein protein
  • binding protein