IMPE Abstracts

Growth is promoted by direct actions of GH on the growth plate and via the actions of GH-stimulated IGF-I production. There are 6 IGF-binding proteins (IGFBPs) that are differentially expressed in tissues and that bind the IGFs. In the circulation, after binding to IGF, IGFBP-3, and -5 also bind with the IGF acid labile subunit (ALS) to form a ternary complex, which increases the half-life of IGF-I. IGF must be liberated from this complex as it is free IGF-I (fIGF-I) that binds to the IGF receptor to activate signaling cascades that up-regulate multiple genes fundamental to the promotion of growth. Human genetic defects in this axis lead to syndromes marked by impaired growth and have helped to further our understanding of growth physiology. Indeed, GH receptor (GHR) mutations cause Laron syndrome with extreme growth failure. Mutations in the STAT5B, IGF-I and IGF-I receptor (IGF-IR) genes cause varying degrees of pre- and postnatal growth retardation and mutations in ALS cause mild short stature. Mutations in IGF2 also affect pre- and postnatal growth. However, to date, no human mutations in the six high-affinity IGFBPs have been reported in association with a monogenic syndrome. In contrast, the ability to release fIGF-I from its association with its binding proteins can be affected. We described three unrelated families with homozygous loss-of-function mutation in PAPPA2, a gene encoding pregnancy-associated plasma protein-A2 (PAPP-A2), a protease highly specific for IGFBP-3 and -5. PAPP-A2 deficiency results in a syndrome of growth retardation with markedly elevated circulating IGF-I and IGF-II levels but decreased fIGF-I concentrations and reduced IGF bioactivity. In addition to a reduced and declining growth velocity, these patients also have thin long bones and decreased lumbar density (Z-score -2 to -2.3 SD). In this conference, the relevance of PAPP-A2 in physiology and disease will be analyzed.