Mice deficient for the OI-gene Kdelr2 display skeletal defects and ER stress attenuable by ascorbic acid

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.