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...

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Detalles Bibliográficos
Autores: 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
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
Descripción
Sumario: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.

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