Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability

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• dc.contributor.author Dauber, Andrewca
• dc.contributor.author Serra Juhé, Clara, 1984-ca
• dc.contributor.author Pérez Jurado, Luis Albertoca
• dc.date.accessioned 2016-04-13T13:30:42Z
• dc.date.available 2016-04-13T13:30:42Z
• dc.date.issued 2016
• dc.description.abstract Mutations in multiple genes of the growth hormone/IGF-I axis have been identified in syndromes marked by growth failure. However, no pathogenic human mutations have been reported in the six high-affinity IGF-binding proteins (IGFBPs) or their regulators, such as the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) that is hypothesized to increase IGF-I bioactivity by specific proteolytic cleavage of IGFBP-3 and -5. Multiple members of two unrelated families presented with progressive growth failure, moderate microcephaly, thin long bones, mildly decreased bone density and elevated circulating total IGF-I, IGFBP-3, and -5, acid labile subunit, and IGF-II concentrations. Two different homozygous mutations in PAPPA2, p.D643fs25* and p.Ala1033Val, were associated with this novel syndrome of growth failure. In vitro analysis of IGFBP cleavage demonstrated that both mutations cause a complete absence of PAPP-A2 proteolytic activity. Size-exclusion chromatography showed a significant increase in IGF-I bound in its ternary complex. Free IGF-I concentrations were decreased. These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP-A2 in releasing IGF-I from its BPs.ca
• dc.description.sponsorship Research reported in this publication was supported by Fondos de Investigación Sanitaria and fondos FEDER (Grants PI100747 and PI1302195 to JA, PI1302481 to LAPJ), Ministerio de Ciencia e Innovación (Grants BFU2011–27492 and BFU2014‐51836‐C2‐2‐R to JAC), Centro de Investigación Biomédica en Red Fisiopatología de Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (JA), Fundación Endocrinología y Nutrición (JA), the Catalan Government (2014SGR1468 and ICREA Acadèmica to LAPJ), the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (Award Number K23HD07335 to AD), The Danish Council for Independent Research (FNU), and the Novo Nordisk Foundation (CO). A CIBER for Rare Diseases (CIBERER) fellowship supported CSJ.
• dc.format.mimetype application/pdfca
• dc.identifier.citation Dauber A, Muñoz-Calvo MT, Barrios V, Domené HM, Kloverpris S, Serra-Juhé C et al. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO molecular medicine. 2016;8(4):363-74. DOI: 10.15252/emmm.201506106ca
• dc.identifier.doi http://dx.doi.org/10.15252/emmm.201506106
• dc.identifier.issn 1757-4676
• dc.identifier.uri http://hdl.handle.net/10230/26077
• dc.language.iso engca
• dc.publisher Wileyca
• dc.relation.ispartof EMBO molecular medicine. 2016;8(4):363-74
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2011-27492
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014‐51836‐C2‐2‐R
• dc.rights © 2016 The Authors. Published under the terms of the CC BY 4.0 licenseca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/ca
• dc.subject.keyword IGF bioavailability
• dc.subject.keyword IGF‐binding proteins
• dc.subject.keyword Bone
• dc.subject.keyword Delayed growth
• dc.subject.keyword Growth hormone
• dc.subject.other Proteïnes -- Fixacióca
• dc.subject.other Hormonesca
• dc.title Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availabilityca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca