2. Academic Validation
  3. Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2

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.
Fleur S van Dijk 1,  Oliver Semler 2,  Julia Etich 3,  Anna Köhler 4,  Juan A Jimenez-Estrada 5,  Nathalie Bravenboer 6,  Lauria Claeys 7,  Elise Riesebos 7,  Sejla Gegic 7,  Sander R Piersma 8,  Connie R Jimenez 8,  Quinten Waisfisz 7,  Carmen-Lisset Flores 5,  Julian Nevado 9,  Arjan J Harsevoort 10,  Guus J M Janus 10,  Anton A M Franken 10,  Astrid M van der Sar 11,  Hanne Meijers-Heijboer 7,  Karen E Heath 12,  Pablo Lapunzina 9,  Peter G J Nikkels 13,  Gijs W E Santen 14,  Julian Nüchel 4,  Markus Plomann 4,  Raimund Wagener 15,  Mirko Rehberg 16,  Heike Hoyer-Kuhn 16,  Elisabeth M W Eekhoff 17,  Gerard Pals 7,  Matthias Mörgelin 18,  Simon Newstead 19,  Brian T Wilson 20,  Victor L Ruiz-Perez 21,  Alessandra Maugeri 7,  Christian Netzer 22,  Frank Zaucke 3,  Dimitra Micha 23
Affiliations

Affiliations

  • 1 Expert Center for Adults with Osteogenesis Imperfecta, Isala Hospital, 10400 Zwolle, the Netherlands; Department of Clinical Genetics, University Medical Center Groningen, 30001 Groningen, the Netherlands; North West Thames Regional Genetics Service, London North West Health Care University NHS Trust, Harrow HA1 3UJ, UK; Department of Metabolism, Digestion and Reproduction, Section of Genetics and Genomics, Imperial College London, London, UK. Electronic address: fleur.dijk@nhs.net.
  • 2 Department of Paediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany; Center for Rare Diseases, University Hospital Cologne, University of Cologne, Cologne 50931, Germany.
  • 3 Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopaedic University Hospital Friedrichsheim gGmbH, Frankfurt/Main 60528, Germany.
  • 4 Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany.
  • 5 Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM), CSIC-UAM, Madrid 28029, Spain.
  • 6 Department of Clinical Chemistry, Amsterdam Movement Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • 7 Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam 1081BT, the Netherlands.
  • 8 Department of Medical Oncology, Cancer center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • 9 Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), ISCIII, Madrid 28029, Spain; Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz-IdiPaz-Universidad Autonóma de Madrid, Madrid 28046, Spain.
  • 10 Expert Center for Adults with Osteogenesis Imperfecta, Isala Hospital, 10400 Zwolle, the Netherlands.
  • 11 Department of Medical Microbiology and Infection Control, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • 12 Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), ISCIII, Madrid 28029, Spain; Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz-IdiPaz-Universidad Autonóma de Madrid, Madrid 28046, Spain; Skeletal Dysplasia Multidisciplinary Unit (UMDE), Hospital Universitario La Paz, Universidad Autonóma de Madrid, Madrid 28046, Spain.
  • 13 Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 14 Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
  • 15 Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne 50931, Germany.
  • 16 Department of Paediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany.
  • 17 Department of Internal Medicine Section Endocrinology, Amsterdam Movement Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • 18 Colzyx AB, Medicon Village, Lund 22381, Sweden.
  • 19 Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
  • 20 North West Thames Regional Genetics Service, London North West Health Care University NHS Trust, Harrow HA1 3UJ, UK; Biosciences Institute, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK.
  • 21 Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM), CSIC-UAM, Madrid 28029, Spain; Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), ISCIII, Madrid 28029, Spain; Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz-IdiPaz-Universidad Autonóma de Madrid, Madrid 28046, Spain.
  • 22 Center for Rare Diseases, University Hospital Cologne, University of Cologne, Cologne 50931, Germany; Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany.
  • 23 Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam 1081BT, the Netherlands. Electronic address: d.micha@amsterdamumc.nl.
PMID: 33053334 DOI: 10.1016/j.ajhg.2020.09.009
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.

Keywords

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

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