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 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

    Research output: Contribution to journalArticlepeer-review


    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 (US)
    Pages (from-to)363-374
    Number of pages12
    JournalEMBO Molecular Medicine
    Issue number4
    StatePublished - Apr 1 2016


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

    ASJC Scopus subject areas

    • Molecular Medicine


    Dive into the research topics of 'Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability'. Together they form a unique fingerprint.

    Cite this