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 Á Martos-Moreno, Federico Hawkins, Héctor G Jasper, Cheryl A Conover, Jan Frystyk, Shoshana Yakar, Vivian Hwa, Julie A Chowen, Claus Oxvig, Ron G Rosenfeld, Luis A Pérez-JuradoJesús Argente

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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.

Original languageEnglish
JournalE M B O Reports
Pages (from-to)363-74
Number of pages12
Publication statusPublished - 2016


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


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