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

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

Abstract 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 metalloproteinase pregna...

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Main Authors: Andrew Dauber, María T Muñoz‐Calvo, Vicente Barrios, Horacio M Domené, Soren Kloverpris, Clara Serra‐Juhé, Vardhini Desikan, Jesús Pozo, Radhika Muzumdar, Gabriel Á Martos‐Moreno, Federico Hawkins, Héctor G Jasper, Cheryl A Conover, Jan Frystyk, Shoshana Yakar, Vivian Hwa, Julie A Chowen, Claus Oxvig, Ron G Rosenfeld, Luis A Pérez‐Jurado, Jesús Argente
Format: Article
Language:English
Published: Springer Nature 2016-02-01
Series:EMBO Molecular Medicine
Subjects:
bone
delayed growth
growth hormone
IGF‐binding proteins
IGF bioavailability
Online Access:https://doi.org/10.15252/emmm.201506106
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Summary:Abstract 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 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 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.
ISSN:1757-4676
1757-4684

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