ABSTRACT
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.
Subject(s)
Bone and Bones/metabolism , Collagen Type I/metabolism , HSP47 Heat-Shock Proteins/metabolism , Osteogenesis Imperfecta/genetics , Vesicular Transport Proteins/metabolism , Adult , Alleles , Amino Acid Sequence , Animals , Binding Sites , Bone and Bones/pathology , Chickens , Child, Preschool , Collagen Type I/chemistry , Collagen Type I/genetics , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/pathology , Female , Fibroblasts/metabolism , Fibroblasts/pathology , Gene Expression , Golgi Apparatus/metabolism , Golgi Apparatus/pathology , HSP47 Heat-Shock Proteins/chemistry , HSP47 Heat-Shock Proteins/genetics , Humans , Infant , Male , Osteogenesis Imperfecta/diagnosis , Osteogenesis Imperfecta/metabolism , Osteogenesis Imperfecta/pathology , Pedigree , Primary Cell Culture , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Protein Transport , Sequence Alignment , Sequence Homology, Amino Acid , Vesicular Transport Proteins/chemistry , Vesicular Transport Proteins/geneticsABSTRACT
Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory properties of PLS3 were supported by in vivo analyses in zebrafish. Furthermore, in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found. This variant was also associated with a risk of fracture among elderly heterozygous women that was two times as high as that among noncarriers, which indicates that genetic variation in PLS3 is a novel etiologic factor involved in common, multi-factorial osteoporosis.
Subject(s)
Fractures, Bone/genetics , Membrane Glycoproteins/genetics , Microfilament Proteins/genetics , Osteoporosis/genetics , Adult , Animals , Bone Density/genetics , Bone Remodeling/genetics , Child , Child, Preschool , Female , Fractures, Bone/etiology , Genetic Diseases, X-Linked/genetics , Heterozygote , Humans , Male , Mutation , Osteoporosis/complications , Pedigree , Polymorphism, Single Nucleotide , Risk Factors , Young Adult , ZebrafishABSTRACT
An expert center for adults with Osteogenesis Imperfecta (OI) has been founded at the Isala Hospital in Zwolle, the Netherlands to achieve optimal care for adults with OI. Clinical data such as patient history, Dual Energy X-ray Absorptiometry measurements and laboratory findings are collected with patient consent. This study provides an overview of clinical characteristics of the patients who visited the clinic during its first 5â¯years, a total of 151 patients. In this study, we focus on bisphosphonate use and bone density measurements at time of presentation at the expert center. As such, insight into the natural history of OI in adults will be increased. Analysing the data of a large group of adults with this rare disorder within a national expert center will allow detailed exploration of the course of OI over time.