TY - JOUR
T1 - Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2
AU - van Dijk, Fleur S.
AU - Semler, Oliver
AU - Etich, Julia
AU - Köhler, Anna
AU - Jimenez-Estrada, Juan A.
AU - Bravenboer, Nathalie
AU - Claeys, Lauria
AU - Riesebos, Elise
AU - Gegic, Sejla
AU - Piersma, Sander R.
AU - Jimenez, Connie R.
AU - Waisfisz, Quinten
AU - Flores, Carmen Lisset
AU - Nevado, Julian
AU - Harsevoort, Arjan J.
AU - Janus, Guus J.M.
AU - Franken, Anton A.M.
AU - van der Sar, Astrid M.
AU - Meijers-Heijboer, Hanne
AU - Heath, Karen E.
AU - Lapunzina, Pablo
AU - Nikkels, Peter G.J.
AU - Santen, Gijs W.E.
AU - Nüchel, Julian
AU - Plomann, Markus
AU - Wagener, Raimund
AU - Rehberg, Mirko
AU - Hoyer-Kuhn, Heike
AU - Eekhoff, Elisabeth M.W.
AU - Pals, Gerard
AU - Mörgelin, Matthias
AU - Newstead, Simon
AU - Wilson, Brian T.
AU - Ruiz-Perez, Victor L.
AU - Maugeri, Alessandra
AU - Netzer, Christian
AU - Zaucke, Frank
AU - Micha, Dimitra
PY - 2020/11/5
Y1 - 2020/11/5
N2 - 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.
AB - 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.
KW - HSP47
KW - KDELR2
KW - osteogenesis imperfecta
KW - retrograde Golgi-ER transport
UR - http://www.scopus.com/inward/record.url?scp=85094975571&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ajhg.2020.09.009
DO - https://doi.org/10.1016/j.ajhg.2020.09.009
M3 - Article
C2 - 33053334
SN - 0002-9297
VL - 107
SP - 989
EP - 999
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -