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

Andrew Dauber, María T. Muñoz-Calvo, Vicente Barrios, Horacio M. Domené, Soren Kloverpris, Clara Serra-Juhé, Vardhini Desikan, Jesús Pozo, Radhika Muzumdar, Gabriel A. Martos-Moreno, Federico Hawkins, Héctor G. Jasper, Cheryl A. Conover, Jan Frystyk, Shoshana Yakar, Vivian Hwa, Julie A. Chowen, Claus Oxvig, Ronald (Ron) Rosenfeld, Luis A. Pérez-JuradoJesús Argente

Research output: Contribution to journalArticle

61 Scopus citations


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.

Original languageEnglish (US)
JournalEMBO Molecular Medicine
StateAccepted/In press - 2016



  • Bone
  • Delayed growth
  • Growth hormone
  • IGF bioavailability
  • IGF-binding proteins

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Dauber, A., Muñoz-Calvo, M. T., Barrios, V., Domené, H. M., Kloverpris, S., Serra-Juhé, C., Desikan, V., Pozo, J., Muzumdar, R., Martos-Moreno, G. A., Hawkins, F., Jasper, H. G., Conover, C. A., Frystyk, J., Yakar, S., Hwa, V., Chowen, J. A., Oxvig, C., Rosenfeld, R. R., ... Argente, J. (Accepted/In press). Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Molecular Medicine.