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

Lookup NU author(s): Dr Brian Wilson, Dr Victor Ruiz-Perez


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© 2020Osteogenesis 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.

Publication metadata

Author(s): van Dijk FS, Semler O, Etich J, Kohler A, Jimenez-Estrada JA, Bravenboer N, Claeys L, Riesebos E, Gegic S, Piersma SR, Jimenez CR, Waisfisz Q, Flores C-L, Nevado J, Harsevoort AJ, Janus GJM, Franken AAM, van der Sar AM, Meijers-Heijboer H, Heath KE, Lapunzina P, Nikkels PGJ, Santen GWE, Nuchel J, Plomann M, Wagener R, Rehberg M, Hoyer-Kuhn H, Eekhoff EMW, Pals G, Morgelin M, Newstead S, Wilson BT, Ruiz-Perez VL, Maugeri A, Netzer C, Zaucke F, Micha D

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2020

Volume: 107

Issue: 5

Pages: 989-999

Print publication date: 05/11/2020

Online publication date: 13/10/2020

Acceptance date: 22/09/2020

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2020.09.009

PubMed id: 33053334


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