Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta

Imagem de Miniatura
Citações na Scopus
Tipo de produção
Data de publicação
Título da Revista
ISSN da Revista
Título do Volume
MOOSA, Shahida
KEUPP, Katharina
MORENO, Carolina Araujo
VALADARES, Eugenia Ribeiro
SOUSA, Sergio B. de
MAIA, Sofia
AMERICAN JOURNAL OF HUMAN GENETICS, v.105, n.4, p.836-843, 2019
Projetos de Pesquisa
Unidades Organizacionais
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, 01-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.
  1. Ai M, 2005, MOL CELL BIOL, V25, P4946, DOI 10.1128/MCB.25.12.4946-4955.2005
  2. Aldinger KA, 2016, J MED GENET, V53, P427, DOI 10.1136/jmedgenet-2015-103476
  3. Chang MK, 2014, J BONE MINER RES, V29, P29, DOI 10.1002/jbmr.2059
  4. Chen JL, 2011, STRUCTURE, V19, P313, DOI 10.1016/j.str.2011.01.010
  5. Culi J, 2004, EMBO J, V23, P1372, DOI 10.1038/sj.emboj.7600132
  6. Culi J, 2003, CELL, V112, P343, DOI 10.1016/S0092-8674(02)01279-5
  7. Day TF, 2005, DEV CELL, V8, P739, DOI 10.1016/j.devcel.2005.03.016
  8. Estrada K, 2012, NAT GENET, V44, P491, DOI 10.1038/ng.2249
  9. Fahiminiya S, 2013, J MED GENET, V50, P345, DOI 10.1136/jmedgenet-2013-101567
  10. Glass DA, 2005, DEV CELL, V8, P751, DOI 10.1016/j.devcel.2005.02.017
  11. Gong YQ, 2001, CELL, V107, P513, DOI 10.1016/S0092-8674(01)00571-2
  12. Hartikka H, 2005, J BONE MINER RES, V20, P783, DOI 10.1359/JBMR.050101
  13. Hill TP, 2005, DEV CELL, V8, P727, DOI 10.1016/j.devcel.2005.02.013
  14. HOLDENER BC, 1994, DEVELOPMENT, V120, P1335
  15. Holmen SL, 2004, J BONE MINER RES, V19, P2033, DOI 10.1359/JBMR.040907
  16. Hsieh JC, 2003, CELL, V112, P355, DOI 10.1016/S0092-8674(03)00045-X
  17. Kedlaya R, 2013, SCI TRANSL MED, V5, DOI 10.1126/scitranslmed.3006627
  18. Kelly OG, 2004, DEVELOPMENT, V131, P2803, DOI 10.1242/dev.01137
  19. Keupp K, 2013, AM J HUM GENET, V92, P565, DOI 10.1016/j.ajhg.2013.02.010
  20. Koduri V, 2007, BIOCHEMISTRY-US, V46, P6570, DOI 10.1021/bi700049g
  21. Laine CM, 2013, NEW ENGL J MED, V368, P1809, DOI 10.1056/NEJMoa1215458
  22. Li YH, 2005, J CELL SCI, V118, P5305, DOI 10.1242/jcs.02651
  23. Lin CH, 2011, FEBS LETT, V585, P3120, DOI 10.1016/j.febslet.2011.08.046
  24. Marini JC, 2017, NAT REV DIS PRIMERS, V3, DOI 10.1038/nrdp.2017.52
  25. Massink MPG, 2015, AM J HUM GENET, V97, P621, DOI 10.1016/j.ajhg.2015.08.014
  26. Trajanoska K, 2019, BONE, V126, P2, DOI 10.1016/j.bone.2019.04.005
  27. Wines ME, 2000, GENOMICS, V68, P322, DOI 10.1006/geno.2000.6264