Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta

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Moosa, Shahida ^{[1, 2]} ; Yamamoto, Guilherme L. ^{[3, 2, 4]} ; Garbes, Lutz ^[5] ; Keupp, Katharina ^{[5, 6, 7]} ; Beleza-Meireles, Ana ^{[8, 9]} ; Moreno, Carolina Araujo ^[10] ; Valadares, Eugenia Ribeiro ; de Sousa, Sergio B. ; Maia, Sofia ; Saraiva, Jorge ; Honjo, Rachel S. ; Kim, Chong Ae ; de Menezes, Hamilton Cabral ; Lausch, Ekkehart ; Lorini, Pablo Villavicencio ; Lamounier, Jr., Arsonval ; Bezerra Carniero, Tulio Canella ; Giunta, Cecilia ; Rohrbach, Marianne ; Janner, Marco ; Semler, Oliver ; Beleggia, Filippo ; Li, Yun ; Yigit, Goekhan ; Reintjes, Nadine ; Altmueller, Janine ; Nuernberg, Peter ; Cavalcanti, Denise P. ; Zabel, Bernhard ; Warman, Matthew L. ; Bertola, Debora R. ; Wollnik, Bernd ^[1] ; Netzer, Christian

Afiliação do(s) autor(es)

^[1] Univ Med Ctr Gottingen, Inst Human Genet, D-37073 Gottingen - Germany

^[2] Boston Childrens Hosp, Dept Orthopaed Surg, Orthopaed Res Labs, Boston, MA 02115 - USA

^[3] Univ Sao Paulo, Inst Biociencias, BR-05508090 Sao Paulo - Brazil

^[4] Univ Sao Paulo, Fac Med, Inst Crianca Hosp Clin, Unidade Genet, BR-05403000 Sao Paulo - Brazil

^[5] Univ Hosp Cologne, Inst Human Genet, D-50931 Cologne - Germany

^[6] Univ Cologne, Fac Med, D-50931 Cologne - Germany

^[7] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Ctr Integrated Oncol, D-50931 Cologne - Germany

^[8] Hosp Pedia Coimbra, Med Genet Unit, Ctr Hosp Univ Coimbra, P-3000602 Coimbra - Portugal

^[9] Univ Hosp Bristol, St Michaels Hosp, Dept Clin Genet, Bristol BS1 3NU, Avon - England

^[10] Univ Fed Minas Gerais, Hosp Clin, Fac Med, BR-30130100 Belo Horizonte, MG - Brazil

• Tipo de documento: Artigo Científico
• Fonte: American Journal of Human Genetics; v. 105, n. 4, p. 836-843, OCT 3 2019.
• Citações Web of Science: 0

Resumo

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. (AU)

• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 15/22145-6 - Contribuição ao estudo clínico-etiológico das displasias esqueléticas e disostoses no Brasil
• Beneficiário: Denise Pontes Cavalcanti
• Modalidade de apoio: Auxílio à Pesquisa - Regular