Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability
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 met alloproteinase pregnancy-asso...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
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| Format: | Article |
| Publication date: | 2016 |
| Country: | España |
| Institution: | Universidad Autónoma de Madrid |
| Repository: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Language: | English |
| OAI Identifier: | oai:repositorio.uam.es:10486/677926 |
| Online Access: | http://hdl.handle.net/10486/677926 https://dx.doi.org/10.15252/emmm.201506106 |
| Access Level: | Open access |
| Keyword: | Bone Delayed growth Growth hormone IGF bioavailability IGF-binding proteins Medicina |
| _version_ | 1878741432811913216 |
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| author | Dauber, Andrew |
| author2 | Muñoz-Calvo, María T. Barrios, Vicente Domené, Horacio M. Kloverpris, Soren Serra-Juhé, Clara Desikan, Vardhini Pozo Román, Jesús Muzumdar, Radhika Martos Moreno, Gabriel Ángel Hawkins, Federico G. Jasper, Héctor G. Conover, Cheryl A. Frystyk, Jan Yakar, Shoshana Hwa, Vivian Chowen, Julie Ann Oxvig, Claus Rosenfeld, Ron G. Pérez-Jurado, Luis A. Argente Oliver, Jesús |
| author2_role | author author author author author author author author author author author author author author author author author author author author |
| author_browse | Argente Oliver, Jesús Barrios, Vicente Chowen, Julie Ann Conover, Cheryl A. Dauber, Andrew Desikan, Vardhini Domené, Horacio M. Frystyk, Jan Hawkins, Federico G. Hwa, Vivian Jasper, Héctor G. Kloverpris, Soren Martos Moreno, Gabriel Ángel Muzumdar, Radhika Muñoz-Calvo, María T. Oxvig, Claus Pozo Román, Jesús Pérez-Jurado, Luis A. Rosenfeld, Ron G. Serra-Juhé, Clara Yakar, Shoshana |
| author_facet | Dauber, Andrew Muñoz-Calvo, María T. Barrios, Vicente Domené, Horacio M. Kloverpris, Soren Serra-Juhé, Clara Desikan, Vardhini Pozo Román, Jesús Muzumdar, Radhika Martos Moreno, Gabriel Ángel Hawkins, Federico G. Jasper, Héctor G. Conover, Cheryl A. Frystyk, Jan Yakar, Shoshana Hwa, Vivian Chowen, Julie Ann Oxvig, Claus Rosenfeld, Ron G. Pérez-Jurado, Luis A. Argente Oliver, Jesús |
| author_role | author |
| collection | Biblos-e Archivo. Repositorio Institucional de la UAM |
| description | 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 met alloproteinase 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_e50da4c6bd0fa5d4e099eb7ecb199e7c |
| institution | Universidad Autónoma de Madrid |
| instname_str | Universidad Autónoma de Madrid |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:repositorio.uam.es:10486/677926 |
| publishDate | 2016 |
| publishDateSort | 2016 |
| publisher | Wiley-Blackwell Publishing Ltd Wiley - V C H Verlag GmbH & Co. KGaA |
| publisherStr | Wiley - V C H Verlag GmbH & Co. KGaA Wiley-Blackwell Publishing Ltd |
| reponame_str | Biblos-e Archivo. Repositorio Institucional de la UAM |
| spelling | Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability Dauber, Andrew Muñoz-Calvo, María T. Barrios, Vicente Domené, Horacio M. Kloverpris, Soren Serra-Juhé, Clara Desikan, Vardhini Pozo Román, Jesús Muzumdar, Radhika Martos Moreno, Gabriel Ángel Hawkins, Federico G. Jasper, Héctor G. Conover, Cheryl A. Frystyk, Jan Yakar, Shoshana Hwa, Vivian Chowen, Julie Ann Oxvig, Claus Rosenfeld, Ron G. Pérez-Jurado, Luis A. Argente Oliver, Jesús Bone Delayed growth Growth hormone IGF bioavailability IGF-binding proteins Medicina 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 met alloproteinase 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. 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 Wiley-Blackwell Publishing Ltd Wiley - V C H Verlag GmbH & Co. KGaA http://hdl.handle.net/10486/677926 https://dx.doi.org/10.15252/emmm.201506106 |
| spellingShingle | Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability Dauber, Andrew Bone Delayed growth Growth hormone IGF bioavailability IGF-binding proteins Medicina |
| title | Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability |
| title_full | Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability |
| title_fullStr | Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability |
| title_full_unstemmed | Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability |
| title_short | Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability |
| title_sort | Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability |
| topic | Bone Delayed growth Growth hormone IGF bioavailability IGF-binding proteins Medicina |
| topic_facet | Bone Delayed growth Growth hormone IGF bioavailability IGF-binding proteins Medicina |
| url | http://hdl.handle.net/10486/677926 https://dx.doi.org/10.15252/emmm.201506106 |