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

Andrew Dauber, María T. Muñoz-Calvo, Vicente Barrios, Horacio M. Domené, Soren Kloverpris, Clara Serra-Juhé, Vardhini Desikan, Jesús Pozo, Radhika Muzumdar, Gabriel A. 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-JuradoJesús Argente

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
JournalEMBO Molecular Medicine
DOIs
StateAccepted/In press - 2016

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Insulin-Like Growth Factor I
varespladib methyl
Blood Proteins
Pregnancy
Mutation
Insulin-Like Growth Factor Binding Protein 5
Insulin-Like Growth Factor Binding Proteins
Insulin-Like Growth Factor Binding Protein 3
Growth
Microcephaly
Insulin-Like Growth Factor II
Metalloproteases
Bone Density
Growth Hormone
Gel Chromatography
Bone and Bones
Acids
Genes

Keywords

  • Bone
  • Delayed growth
  • Growth hormone
  • IGF bioavailability
  • IGF-binding proteins

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Dauber, A., Muñoz-Calvo, M. T., Barrios, V., Domené, H. M., Kloverpris, S., Serra-Juhé, C., ... Argente, J. (Accepted/In press). Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201506106

Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. / Dauber, Andrew; Muñoz-Calvo, María T.; Barrios, Vicente; Domené, Horacio M.; Kloverpris, Soren; Serra-Juhé, Clara; Desikan, Vardhini; Pozo, Jesús; Muzumdar, Radhika; Martos-Moreno, Gabriel A.; Hawkins, Federico; Jasper, Héctor G.; Conover, Cheryl A; Frystyk, Jan; Yakar, Shoshana; Hwa, Vivian; Chowen, Julie A.; Oxvig, Claus; Rosenfeld, Ron G.; Pérez-Jurado, Luis A.; Argente, Jesús.

In: EMBO Molecular Medicine, 2016.

Research output: Contribution to journalArticle

Dauber, A, Muñoz-Calvo, MT, Barrios, V, Domené, HM, Kloverpris, S, Serra-Juhé, 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, Pérez-Jurado, LA & Argente, J 2016, 'Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability', EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201506106
Dauber, Andrew ; Muñoz-Calvo, María T. ; Barrios, Vicente ; Domené, Horacio M. ; Kloverpris, Soren ; Serra-Juhé, Clara ; Desikan, Vardhini ; Pozo, Jesús ; Muzumdar, Radhika ; Martos-Moreno, Gabriel A. ; Hawkins, Federico ; Jasper, Héctor G. ; Conover, Cheryl A ; Frystyk, Jan ; Yakar, Shoshana ; Hwa, Vivian ; Chowen, Julie A. ; Oxvig, Claus ; Rosenfeld, Ron G. ; Pérez-Jurado, Luis A. ; Argente, Jesús. / Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. In: EMBO Molecular Medicine. 2016.
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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 A.

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

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