Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport. Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media. Electron microscopy identified an abnormal quality of secreted collagen fibrils with increased amount of HSP47 bound to monomeric and multimeric collagen molecules. Mapping the identified KDELR2 variants onto the crystal structure of G. gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport. Therefore, in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I. Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation. This highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KDELR2-associated pathogenic mechanism leading to OI.

成骨不全症（OI）的主要特征是对有或没有骨变形的骨折易感性。OI在遗传上是异质的：已识别出20多种遗传原因。我们确定了双等位基因致病性KDELR2变异是四个家庭发生OI的原因。KDELR2编码KDEL内质网蛋白保留受体2，该受体利用顺式的KDEL样肽回收内质网蛋白-通过COPI逆行运输将高尔基运送到ER。对患者原代成纤维细胞的分析显示，培养基中HSP47和FKBP65的细胞内减少，同时I型胶原原减少。电子显微镜鉴定出分泌的胶原纤维的异常质量，其与单体和多聚体胶原分子结合的HSP47数量增加。映射所识别的KDELR2变体到的晶体结构G.鸡KDELR2表明，这些导致失活的受体，导致KDELR2介导的高尔基体-ER运输受损。因此，在缺乏KDELR2的个体中，最有可能发生OI，因为HSP47无法结合KDELR2并与I型胶原蛋白解离。相反，HSP47仍与细胞外的胶原蛋白分子结合，从而破坏了纤维的形成。这突出了ER驻留分子伴侣对I型胶原和骨代谢的细胞内再循环的重要性，以及HSP47在导致OI的与KDELR2相关的致病机制中的关键作用。