Mutations in PAPPA2: growth impairment due to decreased IGF-I bioavailability
IGF-I circulates in a ternary complex composed of IGF binding protein (IGFBP)-3 or IGFBP-5, and acid labile subunit (ALS). This ternary complex protects both the IGF-I and IGFBPs during delivery to target tissues. We recently described the first human mutations in pappalysin 2, PAPPA2, a protease found in the circulation and known to proteolyze IGFBP-5 and IGFBP3. The two mutations identified are recessive, with affected children having total plasma IGF-I and IGFBP3 concentrations well above normal yet presenting with significant short stature. The missense mutation our group identified modestly affected protein expression but destroyed its protease activities. Our patients have not responded well to recombinant human growth hormone (rhGH), and one of the patient is currently undergoing a trial of recombinant IGF-I therapy. A knock-in mouse model of the missense mutation recapitulated the human phenotype and biochemistries. The therapeutic potential of PAPPA2 is being investigated.