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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorMOOSA, Shahida
dc.contributor.authorYAMAMOTO, Guilherme L.
dc.contributor.authorGARBES, Lutz
dc.contributor.authorKEUPP, Katharina
dc.contributor.authorBELEZA-MEIRELES, Ana
dc.contributor.authorMORENO, Carolina Araujo
dc.contributor.authorVALADARES, Eugenia Ribeiro
dc.contributor.authorSOUSA, Sergio B. de
dc.contributor.authorMAIA, Sofia
dc.contributor.authorSARAIVA, Jorge
dc.contributor.authorHONJO, Rachel S.
dc.contributor.authorKIM, Chong Ae
dc.contributor.authorMENEZES, Hamilton Cabral de
dc.contributor.authorLAUSCH, Ekkehart
dc.contributor.authorLORINI, Pablo Villavicencio
dc.contributor.authorLAMOUNIER JR., Arsonval
dc.contributor.authorCARNIERO, Tulio Canella Bezerra
dc.contributor.authorGIUNTA, Cecilia
dc.contributor.authorROHRBACH, Marianne
dc.contributor.authorJANNER, Marco
dc.contributor.authorSEMLER, Oliver
dc.contributor.authorBELEGGIA, Filippo
dc.contributor.authorLI, Yun
dc.contributor.authorYIGIT, Goekhan
dc.contributor.authorREINTJES, Nadine
dc.contributor.authorALTMUELLER, Janine
dc.contributor.authorNUERNBERG, Peter
dc.contributor.authorCAVALCANTI, Denise P.
dc.contributor.authorZABEL, Bernhard
dc.contributor.authorWARMAN, Matthew L.
dc.contributor.authorBERTOLA, Debora R.
dc.contributor.authorWOLLNIK, Bernd
dc.contributor.authorNETZER, Christian
dc.identifier.citationAMERICAN JOURNAL OF HUMAN GENETICS, v.105, n.4, p.836-843, 2019
dc.description.abstractOsteogenesis 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.eng
dc.description.sponsorshipDeutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence StrategyGerman Research Foundation (DFG) [EXC 2067/1-390729940]
dc.description.sponsorshipSao Paulo Research Foundation (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2015/22145-6]
dc.description.sponsorshipSwiss National Science FoundationSwiss National Science Foundation (SNSF) [31003A-173183]
dc.description.sponsorshipFAPESPFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2015/22145-6, 2013/08028-1]
dc.description.sponsorshipCentro de Pesquisa, Inovacao e Difusao (CEPID) [2013/08028-1]
dc.description.sponsorshipBrazilian National Council for Scientific and Technological Development (CNPq)National Council for Scientific and Technological Development (CNPq) [304130/2016-8]
dc.description.sponsorshipCNPqNational Council for Scientific and Technological Development (CNPq) [236670/2012-3]
dc.description.sponsorshipNIAMSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [5R01-AR053237-12, R01-AR064231]
dc.description.sponsorshipDFGGerman Research Foundation (DFG) [FOR 2722]
dc.publisherCELL PRESSeng
dc.relation.ispartofAmerican Journal of Human Genetics
dc.subject.otherreceptor-related protein-6eng
dc.titleAutosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfectaeng
dc.rights.holderCopyright CELL PRESSeng
dc.subject.wosGenetics & Heredityeng
dc.type.categoryoriginal articleeng
dc.type.versionpublishedVersioneng, Shahida:Univ Med Ctr Gottingen, Inst Human Genet, D-37073 Gottingen, Germany; Boston Childrens Hosp, Dept Orthopaed Surg, Orthopaed Res Labs, Boston, MA 02115 USA, Lutz:Univ Hosp Cologne, Inst Human Genet, D-50931 Cologne, Germany, Katharina:Univ Hosp Cologne, Inst Human Genet, D-50931 Cologne, Germany; Univ Cologne, Fac Med, D-50931 Cologne, Germany; Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Ctr Integrated Oncol, D-50931 Cologne, Germany, Ana:Hosp Pedia Coimbra, Med Genet Unit, Ctr Hosp Univ Coimbra, P-3000602 Coimbra, Portugal; Univ Hosp Bristol, St Michaels Hosp, Dept Clin Genet, Bristol BS1 3NU, Avon, England, Carolina Araujo:Univ Fed Minas Gerais, Hosp Clin, Fac Med, BR-30130100 Belo Horizonte, MG, Brazil, Bernd:Univ Med Ctr Gottingen, Inst Human Genet, D-37073 Gottingen, Germany
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Artigos e Materiais de Revistas Científicas - FM/MPE
Departamento de Pediatria - FM/MPE

Artigos e Materiais de Revistas Científicas - HC/ICr
Instituto da Criança - HC/ICr

Artigos e Materiais de Revistas Científicas - LIM/03
LIM/03 - Laboratório de Medicina Laboratorial

Artigos e Materiais de Revistas Científicas - LIM/36
LIM/36 - Laboratório de Pediatria Clínica

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