TY - JOUR
T1 - Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability
AU - Dauber, Andrew
AU - Muñoz-Calvo, María T.
AU - Barrios, Vicente
AU - Domené, Horacio M.
AU - Kloverpris, Soren
AU - Serra-Juhé, Clara
AU - Desikan, Vardhini
AU - Pozo, Jesús
AU - Muzumdar, Radhika
AU - Martos-Moreno, Gabriel
AU - Hawkins, Federico
AU - Jasper, Héctor G.
AU - Conover, Cheryl A.
AU - Frystyk, Jan
AU - Yakar, Shoshana
AU - Hwa, Vivian
AU - Chowen, Julie A.
AU - Oxvig, Claus
AU - Rosenfeld, Ron G.
AU - Pérez-Jurado, Luis A.
AU - Argente, Jesús
N1 - Publisher Copyright:
© 2016 EMBO.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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.
KW - Bone
KW - Delayed growth
KW - Growth hormone
KW - IGF bioavailability
KW - IGF-binding proteins
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U2 - 10.15252/emmm.201506106
DO - 10.15252/emmm.201506106
M3 - Article
C2 - 26902202
AN - SCOPUS:84958719383
SN - 1757-4676
VL - 8
SP - 363
EP - 374
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 4
ER -