van Dijk, Fleur S., Semler, Oliver, Etich, Julia ORCID: 0000-0003-3238-6692, Koehler, Anna, Jimenez-Estrada, Juan A., Bravenboer, Nathalie, Claeys, Lauria, Riesebos, Elise, Gegic, Sejla, Piersma, Sander R., Jimenez, Connie R., Waisfisz, Quinten, Flores, Carmen-Lisset ORCID: 0000-0002-2439-5030, Nevado, Julian, Harsevoort, Arjan J., Janus, Guus J. M., Franken, Anton A. M., van der Sar, Astrid M., Meijers-Heijboer, Hanne, Heath, Karen E., Lapunzina, Pablo, Nikkels, Peter G. J., Santen, Gijs W. E., Nuechel, Julian, Plomann, Markus, Wagener, Raimund, Rehberg, Mirko, Hoyer-Kuhn, Heike, Eekhoff, Elisabeth M. W., Pals, Gerard, Morgelin, Matthias, Newstead, Simon, Wilson, Brian T., Ruiz-Perez, Victor L., Maugeri, Alessandra, Netzer, Christian, Zaucke, Frank and Micha, Dimitra ORCID: 0000-0001-7890-4411 (2020). Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2. Am. J. Hum. Genet., 107 (5). S. 989 - 1000. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
van Dijk, Fleur S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Semler, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Etich, JuliaUNSPECIFIEDorcid.org/0000-0003-3238-6692UNSPECIFIED
Koehler, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jimenez-Estrada, Juan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bravenboer, NathalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claeys, LauriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riesebos, EliseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gegic, SejlaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piersma, Sander R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jimenez, Connie R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waisfisz, QuintenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flores, Carmen-LissetUNSPECIFIEDorcid.org/0000-0002-2439-5030UNSPECIFIED
Nevado, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harsevoort, Arjan J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janus, Guus J. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franken, Anton A. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Sar, Astrid M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meijers-Heijboer, HanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heath, Karen E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lapunzina, PabloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nikkels, Peter G. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Santen, Gijs W. E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuechel, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plomann, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagener, RaimundUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rehberg, MirkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoyer-Kuhn, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eekhoff, Elisabeth M. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pals, GerardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morgelin, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Newstead, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wilson, Brian T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruiz-Perez, Victor L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maugeri, AlessandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Netzer, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zaucke, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Micha, DimitraUNSPECIFIEDorcid.org/0000-0001-7890-4411UNSPECIFIED
URN: urn:nbn:de:hbz:38-312043
DOI: 10.1016/j.ajhg.2020.09.009
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 107
Number: 5
Page Range: S. 989 - 1000
Date: 2020
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GOLGI; COMPONENTS; MUTATIONSMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/31204

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