ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Endocrinology. 2019;160:1363–1376.

Pregnancy-associated plasma protein A2 (PAPP-A2) is a metalloproteinase which, by cleaving IGFBP-3 and IGFBP-5, releases free IGF-I from the ternary complexes and regulates its bioavailability. PAPPA2 gene mutations (p.D643fs25* and p.Ala1033Val) have recently been described in various members of two unrelated families. Affected patients have short stature, moderate microcephaly, thin long bones, mildly decreased bone density, insulin resistance, elevated total IGF-I and IGFBP-3 but low free IGF-I [1].

In this study, a mouse model harboring the human Pappa2 p.Ala1033V mutation was generated using a knock-in strategy, leading to detectable protein levels of PAPP-A2 but without protease activities. Animals underwent a thorough characterization including anthropometry, glucose and insulin tolerance test, hormonal assessments (total IGF-I, free IGF-I, intact IGFBP-3, GH, insulin, ALS and PAPPA2), bone morphology and bone mineral density evaluation.

Pappa2 mutation homozygous mice showed clinical features resembling those of patients: reduced body length and weight, higher liver weight associated with elevated IGFALS levels, higher fat mass percentage, slender bones and decreased bone length, and insulin resistance. Consistent with human data, although total IGF-I levels were increased, free IGF-I was reduced, thus explaining the impaired growth. The presence of insulin resistance may be secondary to GH hypersecretion, caused by the impaired IGF-I (i.e. less free IGF-I) negative feedback on pituitary. An alternative or complementary explanation for insulin resistance is the impaired IGF-I signaling secondary to reduced IGF-I bioavailability. Human IGF-I has ~50% homology with pro-insulin and can bind to both the IGF-I receptor (IGF1R) and, with reduced affinity, the insulin receptor (IR). Free IGF-I can signal via IGF-IR, insulin receptor or an insulin/IGF-IR hybrid receptor, stimulating the glucose transport into the muscle. Therefore, low free IGF-I levels in PAPP-A2 deficiency could per se contribute to insulin resistance.

Overall, these findings clearly show a close similarity between Pappa2 mutation knock-in animals and the clinical picture of patients with PAPPA2 mutations. This animal model could be used to test new therapeutic options such as PAPP-A2 administration to increase free IGF-I levels in the cases of PAPP-A2 deficiency and, potentially, in patients with other conditions associated with severe short stature [2].

References: 1. Dauber A, Munoz-Calvo MT, Barrios V, Domene HM, Kloverpris S, Serra-Juhe C, Desikan V, Pozo J, Muzumdar R, Martos-Moreno GA, Hawkins F, Jasper HG, Conover CA, Frystyk J, Yakar S, Hwa V, Chowen JA, Oxvig C, Rosenfeld RG, Perez-Jurado LA, Argente J. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol Med 2016;8:363–374.

2. Andrew M, Liao L, Fujimoto M, Khoury J, Hwa V, Dauber A. PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: in vivo and in vitro Evidence. J Endocr Soc 2018;2:646–656.