dc.contributor.author |
Dauber, Andrew |
dc.contributor.author |
Serra Juhé, Clara, 1984- |
dc.contributor.author |
Pérez Jurado, Luis Alberto |
dc.date |
2016 |
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): 363-374. DOI 10.15252/emmm.201506106 |
dc.identifier.citation |
1757-4676 |
dc.identifier.citation |
http://dx.doi.org/10.15252/emmm.201506106 |
dc.identifier.uri |
http://hdl.handle.net/10230/26077 |
dc.format |
application/pdf |
dc.language.iso |
eng |
dc.publisher |
Wiley |
dc.relation |
EMBO molecular medicine. 2016; 8(4): 363-374 |
dc.rights |
© 2016 The Authors. Published under the terms of the CC BY 4.0 license |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.rights |
http://creativecommons.org/licenses/by/4.0/ |
dc.subject |
Proteïnes -- Fixació |
dc.subject |
Hormones |
dc.subject |
IGF bioavailability |
dc.subject |
IGF‐binding proteins |
dc.subject |
Bone |
dc.subject |
Delayed growth |
dc.subject |
Growth hormone |
dc.title |
Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability |
dc.type |
info:eu-repo/semantics/article |
dc.type |
info:eu-repo/semantics/publishedVersion |
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. |
dc.description.abstract |
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. |