Evidence map›Paper›PMID 31564437›Full record

ArticleAmerican journal of human genetics2019

Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta.

Shahida Moosa, Guilherme L Yamamoto, Lutz Garbes, Katharina Keupp, Ana Beleza-Meireles, Carolina Araujo Moreno, Eugenia Ribeiro Valadares, Sérgio B de Sousa, Sofia Maia, Jorge Saraiva and 23 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.

0numbers the graph read from it
0cells of the map it votes in
36citing papers in PubMed
6.3field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

36 citing papers in PubMed, 64 citations in OpenAlex.

  1. Review
  2. Review
  3. Article
  4. Review
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  6. Review
  7. An inducible mouse model of osteogenesis imperfecta type V reveals aberrant osteogenesis caused by Ifitm5 c.-14C>T mutation.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2025
    Article
  8. Article
  9. Review
  10. Update on the Genetics of Osteogenesis Imperfecta.Calcified tissue international · 2024
    Review
  11. Review
  12. Article
  13. Review
  14. Current Status of Next-Generation Sequencing in Bone Genetic Diseases.International journal of molecular sciences · 2023
    Review
  15. Review
  16. Review
  17. Article
  18. Tooth number abnormality: from bench to bedside.International journal of oral science · 2023
    Review
  19. Mutant MESD links cellular stress to type I collagen aggregation in osteogenesis imperfecta type XX.Matrix biology : journal of the International Society for Matrix Biology · 2023
    Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

33 authors at 11 institutions in 6 countries.

Shahida MoosaInstitute 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.
Guilherme L YamamotoOrthopaedic 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.
Lutz GarbesInstitute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany; Faculty of Medicine, University of Cologne, 50931 Cologne, Germany.
Katharina KeuppInstitute 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.
Ana Beleza-MeirelesMedical 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.
Carolina Araujo MorenoSkeletal Dysplasia Group, Department of Medical Genetics, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, 13083-887, Brazil.
Eugenia Ribeiro ValadaresHospital 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.
Sérgio B de SousaMedical 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.
Sofia MaiaMedical 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.
Jorge SaraivaMedical 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.
Rachel S HonjoUnidade de Genética, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, 05403-000, Brazil.
Chong Ae KimInstituto de Biociências da Universidade de São Paulo, São Paulo, 05508-090, Brazil.
Hamilton Cabral de MenezesUnidade de Endocrinologia, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, 05403-000, Brazil.
Ekkehart LauschDivision of Genetics, Children's Hospital, University of Freiburg, 79106 Freiburg, Germany.
Pablo Villavicencio LoriniDivision 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.
Arsonval LamounierHospital das Clínicas da Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil.
Tulio Canella Bezerra CarnieroHospital das Clínicas da Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Brazil.
Cecilia GiuntaConnective Tissue Unit, Division of Metabolism, University Children's Hospital Zurich, 8032 Zurich, Switzerland.
Marianne RohrbachConnective Tissue Unit, Division of Metabolism, University Children's Hospital Zurich, 8032 Zurich, Switzerland.
Marco JannerDivision of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, CH-3010 Bern, Switzerland.
Oliver SemlerFaculty of Medicine, University of Cologne, 50931 Cologne, Germany; Department of Pediatrics, University Hospital Cologne, 50931 Cologne, Germany.
Filippo BeleggiaInstitute 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.
Yun LiInstitute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.
Gökhan YigitInstitute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.
Nadine ReintjesInstitute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany; Faculty of Medicine, University of Cologne, 50931 Cologne, Germany.
Janine AltmüllerCologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
Peter NürnbergCologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
Denise P CavalcantiSkeletal Dysplasia Group, Department of Medical Genetics, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, 13083-887, Brazil.
Bernhard ZabelDivision of Genetics, Children's Hospital, University of Freiburg, 79106 Freiburg, Germany; Medical Faculty of the University of Magdeburg, 39120 Magdeburg, Germany.
Matthew L WarmanOrthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Debora R BertolaUnidade 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.
Bernd WollnikInstitute 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: bernd.wollnik@med.uni-goettingen.de.
Christian NetzerInstitute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany; Faculty of Medicine, University of Cologne, 50931 Cologne, Germany.
University of Cologne · DEHospitais da Universidade de Coimbra · PTUniversity of Freiburg · DEBoston Children's Hospital · USUniversitätsmedizin Göttingen · DEHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo · BRHospital das Clínicas da Universidade Federal de Minas Gerais · BRUniversidade de São Paulo · BRUniversidade Estadual de Campinas (UNICAMP) · BRUniversity Children's Hospital Zurich · CHUniversity Hospital of Bern · CH

Funding

Lrp5 signaling in bone mechanotransduction and metabolismR01AR053237 · NIAMS · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI ALEXANDER G ROBLING, Matthew L Warman · 2005 to 2026
$9.4M
Non-heritable genetic diseases of the skeletal system: Pathogenesis and TreatmentR01AR064231 · NIAMS · BOSTON CHILDREN'S HOSPITAL · PI WARMAN, MATTHEW L · 2014 to 2018
$1.9M
NIAMS NIH HHS R01 AR053237NIAMS NIH HHS R01 AR064231
6 · The paper itself

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.

Indexed as

MutationAnimalsFemaleGenes, RecessiveHEK293 CellsHumansLow Density Lipoprotein Receptor-Related Protein-5Low Density Lipoprotein Receptor-Related Protein-6MaleMiceMolecular ChaperonesOsteogenesis ImperfectaPedigreePhenotypeWnt Signaling PathwayLow Density Lipoprotein Receptor-Related Protein-5Low Density Lipoprotein Receptor-Related Protein-6LRP5 protein, humanLRP6 protein, humanMESD protein, humanMolecular ChaperonesMESDosteogenesis imperfectaWNT signaling

Identifiers

PMID31564437
PMCPMC6817720
OpenAlexW2975577671

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.