Open AccessMutations in pregnancy‐associated plasma protein A2 cause short stature due to low IGF ‐I availability
Author(s) -
Dauber Andrew,
MuñozCalvo María T,
Barrios Vicente,
Domené Horacio M,
Kloverpris Soren,
SerraJuhé Clara,
Desikan Vardhini,
Pozo Jesús,
Muzumdar Radhika,
MartosMoreno Gabriel Á,
Hawkins Federico,
Jasper Héctor G,
Conover Cheryl A,
Frystyk Jan,
Yakar Shoshana,
Hwa Vivian,
Chowen Julie A,
Oxvig Claus,
Rosenfeld Ron G,
PérezJurado Luis A,
Argente Jesús
Publication year - 2016
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201506106
Subject(s) - short stature , medicine , pediatric endocrinology , pediatrics , library science , humanities , gerontology , art , computer science
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 ( IGFBP s) or their regulators, such as the metalloproteinase 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 PAPPA 2 , 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 BP s.