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...
| Autores: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | Universidad Autónoma de Madrid |
| Repositorio: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.uam.es:10486/677926 |
| Acceso en línea: | http://hdl.handle.net/10486/677926 https://dx.doi.org/10.15252/emmm.201506106 |
| Access Level: | acceso abierto |
| Palabra clave: | Bone Delayed growth Growth hormone IGF bioavailability IGF-binding proteins Medicina |
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Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availabilityDauber, AndrewMuñoz-Calvo, María T.Barrios, VicenteDomené, Horacio M.Kloverpris, SorenSerra-Juhé, ClaraDesikan, VardhiniPozo Román, JesúsMuzumdar, RadhikaMartos Moreno, Gabriel ÁngelHawkins, Federico G.Jasper, Héctor G.Conover, Cheryl A.Frystyk, JanYakar, ShoshanaHwa, VivianChowen, Julie AnnOxvig, ClausRosenfeld, Ron G.Pérez-Jurado, Luis A.Argente Oliver, JesúsBoneDelayed growthGrowth hormoneIGF bioavailabilityIGF-binding proteinsMedicinaMutations 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 CSJWiley-Blackwell Publishing LtdWiley - V C H Verlag GmbH & Co. KGaADepartamento de PediatríaFacultad de MedicinaInstituto de Investigación del Hospital de La Princesa (IP)20162016-04-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/677926https://dx.doi.org/10.15252/emmm.201506106reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6779262026-06-23T12:46:27Z |
| dc.title.none.fl_str_mv |
Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability |
| title |
Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability |
| 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_short |
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_sort |
Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability |
| dc.creator.none.fl_str_mv |
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 |
Dauber, Andrew |
| 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 |
| 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 |
| dc.contributor.none.fl_str_mv |
Departamento de Pediatría Facultad de Medicina Instituto de Investigación del Hospital de La Princesa (IP) |
| dc.subject.none.fl_str_mv |
Bone Delayed growth Growth hormone IGF bioavailability IGF-binding proteins Medicina |
| topic |
Bone Delayed growth Growth hormone IGF bioavailability IGF-binding proteins Medicina |
| 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. |
| publishDate |
2016 |
| dc.date.none.fl_str_mv |
2016 2016-04-01 |
| dc.type.none.fl_str_mv |
research article http://purl.org/coar/resource_type/c_2df8fbb1 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10486/677926 https://dx.doi.org/10.15252/emmm.201506106 |
| url |
http://hdl.handle.net/10486/677926 https://dx.doi.org/10.15252/emmm.201506106 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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application/pdf |
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Wiley-Blackwell Publishing Ltd Wiley - V C H Verlag GmbH & Co. KGaA |
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Wiley-Blackwell Publishing Ltd Wiley - V C H Verlag GmbH & Co. KGaA |
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reponame:Biblos-e Archivo. Repositorio Institucional de la UAM instname:Universidad Autónoma de Madrid |
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Universidad Autónoma de Madrid |
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Biblos-e Archivo. Repositorio Institucional de la UAM |
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