PDF(Pubmed)
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.
摘要：
极度近视（EM），定义为球面当量(SE)≤-10.00屈光度(D)，是视力损害的主要原因之一。已知的EM相关变异只能解释有限的风险，不足以用于临床决策。为了发现风险基因，我们对449例EM个体和9606例对照进行了全外显子组测序(WES).我们在EM病例中发现了大量罕见的蛋白质截断变体（PTV），富集在逆行囊泡介导的转运途径中。采用单细胞RNA测序（scRNA-seq）和单细胞多基因负荷评分（scPBS），我们确定PI16+/SFRP4+成纤维细胞是最相关的细胞类型。我们观察到KDELR3在巩膜成纤维细胞中高表达，并参与巩膜细胞外基质（ECM）组织。斑马鱼模型显示，kdelr3下调导致眼轴长度延长和晶状体直径增加。一起,我们的研究提供了人类EM遗传学的见解，并强调了KDELR3在EM发病机制中的作用。
