Juan A. Jiménez‐Estrada, Carmen‐Lisset Flores, Almudena Fernández, Asier Iturrate, Anja Niehoff, Maren Dreiner, Giulio Gatto, Marta Cantero, Alice Stephan, Aránzazu Mediero, Gabriel Herrero‐Beaumont, Raquel Largo, Oliver Semler, Frank Zaucke, Pablo Lapunzina, Lluı́s Montoliu, Víctor L. Ruiz‐Pérez
Abstract KDELR2 encodes a cis-Golgi membrane receptor that functions recycling endoplasmic reticulum (ER) proteins bearing a C-terminal KDEL-like sequence. Pathogenic variants in this gene have previously been associated with osteogenesis imperfecta (OI). Herein, we studied the phenotype of Kdelr2 -knockout mice both at the tissue and cellular level. Kdelr2 −/− mice displayed neonatal lethality and were identified at the final embryonic stages with bones of reduced length, delayed ossification, and reduced connectivity density. Evaluation of the secretome of Kdelr2 −/− mouse embryonic fibroblasts (MEFs) using mass spectrometry revealed that loss of KDELR2 leads to massive secretion of ER-resident proteins including OI-associated enzymes and chaperones. Whole-transcriptome expression profiling of these cells also identified ER stress and an active unfolded protein response. Notably, the deleterious effects observed in Kdelr2 −/− MEFs were alleviated by supplementing their culture medium with ascorbic acid or by the overexpression of KDELR1 or KDELR3; thus, exposing therapeutic possibilities to treat this disease.