Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2

Am J Hum Genet. 2020 Nov 5;107(5):989-999. doi: 10.1016/j.ajhg.2020.09.009. Epub 2020 Oct 13.


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.

Keywords: HSP47; KDELR2; osteogenesis imperfecta; retrograde Golgi-ER transport.

MeSH terms

  • Adult
  • Alleles
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Bone and Bones / metabolism*
  • Bone and Bones / pathology
  • Chickens
  • Child, Preschool
  • Collagen Type I / chemistry
  • Collagen Type I / genetics
  • Collagen Type I / metabolism*
  • 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
  • HSP47 Heat-Shock Proteins / metabolism*
  • Humans
  • Infant
  • Male
  • Osteogenesis Imperfecta / diagnosis
  • Osteogenesis Imperfecta / genetics*
  • 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 / genetics
  • Vesicular Transport Proteins / metabolism*


  • Collagen Type I
  • HSP47 Heat-Shock Proteins
  • SERPINH1 protein, human
  • Vesicular Transport Proteins
  • KDELR2 protein, human