2. Academic Validation
  3. Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta

Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta

  • Am J Hum Genet. 2019 Oct 3;105(4):836-843. doi: 10.1016/j.ajhg.2019.08.008.
Shahida Moosa 1,  Guilherme L Yamamoto 2,  Lutz Garbes 3,  Katharina Keupp 4,  Ana Beleza-Meireles 5,  Carolina Araujo Moreno 6,  Eugenia Ribeiro Valadares 7,  Sérgio B de Sousa 8,  Sofia Maia 8,  Jorge Saraiva 9,  Rachel S Honjo 10,  Chong Ae Kim 11,  Hamilton Cabral de Menezes 12,  Ekkehart Lausch 13,  Pablo Villavicencio Lorini 14,  Arsonval Lamounier Jr 15,  Tulio Canella Bezerra Carniero 15,  Cecilia Giunta 16,  Marianne Rohrbach 16,  Marco Janner 17,  Oliver Semler 18,  Filippo Beleggia 19,  Yun Li 20,  Gökhan Yigit 20,  Nadine Reintjes 3,  Janine Altmüller 21,  Peter Nürnberg 21,  Denise P Cavalcanti 6,  Bernhard Zabel 22,  Matthew L Warman 23,  Debora R Bertola 24,  Bernd Wollnik 25,  Christian Netzer 3
Affiliations

Affiliations

  • 1 Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany; Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 2 Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Unidade de Genética, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, 05403-000, Brazil; Instituto de Biociências da Universidade de São Paulo, São Paulo, 05508-090, Brazil.
  • 3 Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany; Faculty of Medicine, University of Cologne, 50931 Cologne, Germany.
  • 4 Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany; Faculty of Medicine, University of Cologne, 50931 Cologne, Germany; Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, University Hospital of Cologne, 50931 Cologne, Germany.
  • 5 Medical Genetics Unit, Hospital Pediátrico de Coimbra, Centro Hospitalar e Universitário de Coimbra, 3000-602 Coimbra, Portugal; Department of Clinical Genetics, St Michael's Hospital, University Hospitals Bristol, BS1 3NU, Bristol, UK.
  • 6 Skeletal Dysplasia Group, Department of Medical Genetics, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, 13083-887, Brazil.
  • 7 Hospital das Clínicas da Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil; Division of Genetics, Children's Hospital, University of Freiburg, 79106 Freiburg, Germany.
  • 8 Medical Genetics Unit, Hospital Pediátrico de Coimbra, Centro Hospitalar e Universitário de Coimbra, 3000-602 Coimbra, Portugal; University Clinic of Genetics, Faculty of Medicine, University of Coimbra, 3000-531 Coimbra, Portugal.
  • 9 Medical Genetics Unit, Hospital Pediátrico de Coimbra, Centro Hospitalar e Universitário de Coimbra, 3000-602 Coimbra, Portugal; University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra, 3000-531 Coimbra, Portugal.
  • 10 Unidade de Genética, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, 05403-000, Brazil.
  • 11 Instituto de Biociências da Universidade de São Paulo, São Paulo, 05508-090, Brazil.
  • 12 Unidade de Endocrinologia, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, 05403-000, Brazil.
  • 13 Division of Genetics, Children's Hospital, University of Freiburg, 79106 Freiburg, Germany.
  • 14 Division of Genetics, Children's Hospital, University of Freiburg, 79106 Freiburg, Germany; Institute of Human Genetics, University Hospital Halle, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany.
  • 15 Hospital das Clínicas da Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil.
  • 16 Connective Tissue Unit, Division of Metabolism, University Children's Hospital Zurich, 8032 Zurich, Switzerland.
  • 17 Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, CH-3010 Bern, Switzerland.
  • 18 Faculty of Medicine, University of Cologne, 50931 Cologne, Germany; Department of Pediatrics, University Hospital Cologne, 50931 Cologne, Germany.
  • 19 Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany; Faculty of Medicine, University of Cologne, 50931 Cologne, Germany; Clinic I of Internal Medicine, University Hospital Cologne, 50931 Cologne, Germany.
  • 20 Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.
  • 21 Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
  • 22 Division of Genetics, Children's Hospital, University of Freiburg, 79106 Freiburg, Germany; Medical Faculty of the University of Magdeburg, 39120 Magdeburg, Germany.
  • 23 Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 24 Unidade de Genética, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, 05403-000, Brazil; Instituto de Biociências da Universidade de São Paulo, São Paulo, 05508-090, Brazil.
  • 25 Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany; Cluster of Excellence, Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells (MBExC), University of Göttingen, 37073 Göttingen, Germany. Electronic address: [email protected].
PMID: 31564437 DOI: 10.1016/j.ajhg.2019.08.008
Abstract

Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (Wnt) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, OI-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical Wnt signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated Wnt signaling could benefit individuals with MESD-associated OI.

Keywords

MESD; WNT signaling; osteogenesis imperfecta.

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