Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability.

MARÍA T MUÑOZ-CALVO; SOREN KLOVERPRIS; JESÚS POZO; FEDERICO HAWKINS; ANDREW DAUBER; JAN FRYSTYK; HORACIO M DOMENÉ; JULIE A CHOWEN; VARDHINI DESIKAN; LUIS A PÉREZ-JURADO; GABRIEL Á MARTOS-MORENO; CHERYL A CONOVER; VIVIAN HWA; RON G ROSENFELD; VICENTE BARRIOS; CLARA SERRA-JUHÉ; RADHIKA MUZUMDAR; HÉCTOR G JASPER; SHOSHANA YAKAR; CLAUS OXVIG; JESÚS ARGENTE

EMBO MOLECULAR MEDICINE

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2016 vol. 31 p. 363 - 374

1757-4676

Mutations in multiple genes of the growth hormone/IGF-I axishave been identified in syndromes marked by growth failure.However, no pathogenic human mutations have been reported inthe six high-affinity IGF-binding proteins (IGFBPs) or their regulators,such as the metalloproteinase pregnancy-associated plasmaprotein A2 (PAPP-A2) that is hypothesized to increase IGF-I bioactivityby specific proteolytic cleavage of IGFBP-3 and -5. Multiplemembers of two unrelated families presented with progressivegrowth failure, moderate microcephaly, thin long bones, mildlydecreased bone density and elevated circulating total IGF-I, IGFBP-3,and -5, acid labile subunit, and IGF-II concentrations. Two differenthomozygous mutations in PAPPA2, p.D643fs25* and p.Ala1033Val,were associated with this novel syndrome of growth failure. Invitro analysis of IGFBP cleavage demonstrated that both mutationscause a complete absence of PAPP-A2 proteolytic activity. Sizeexclusionchromatography showed a significant increase in IGF-Ibound in its ternary complex. Free IGF-I concentrations weredecreased. These patients provide important insights into theregulation of longitudinal growth in humans, documenting thecritical role of PAPP-A2 in releasing IGF-I from its BPs.