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

EMBO Mol Med. 2016 Apr 1;8(4):363-74. doi: 10.15252/emmm.201506106.

Andrew Dauber ¹, María T Muñoz-Calvo ², Vicente Barrios ², Horacio M Domené ³, Soren Kloverpris ⁴, Clara Serra-Juhé ⁵, Vardhini Desikan ⁶, Jesús Pozo ², Radhika Muzumdar ⁷, Gabriel Á Martos-Moreno ², Federico Hawkins ⁸, Héctor G Jasper ³, Cheryl A Conover ⁹, Jan Frystyk ¹⁰, Shoshana Yakar ¹¹, Vivian Hwa ¹, Julie A Chowen ², Claus Oxvig ⁴, Ron G Rosenfeld ¹², Luis A Pérez-Jurado ⁵, Jesús Argente ¹³

Affiliations

1 Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
2 Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús Instituto de Investigación La Princesa Universidad Autónoma de Madrid, Madrid, Spain Program of Pediatric Obesity, CIBEROBN Instituto de Salud Carlos III, Madrid, Spain.
3 Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET, FEI, División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
4 Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
5 Genetics Unit, Universitat Pompeu Fabra Hospital del Mar Research Institute (IMIM) & CIBERER. Instituto de Salud Carlos III, Barcelona, Spain.
6 Department of Pediatrics, Division of Pediatric Endocrinology, New York Medical College, Valhalla NY, USA.
7 Division of Endocrinology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
8 Department of Endocrinology, Hospital Universitario 12 de Octubre Universidad Complutense de Madrid, Madrid, Spain.
9 Division of Endocrinology, Mayo Clinic, Rochester, MN, USA.
10 Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
11 Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA.
12 Oregon Health and Science University, Portland, OR, USA STAT5 LLC, Los Altos, CA, USA.
13 Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús Instituto de Investigación La Princesa Universidad Autónoma de Madrid, Madrid, Spain Program of Pediatric Obesity, CIBEROBN Instituto de Salud Carlos III, Madrid, Spain jesus.argente@uam.es.

PMID: 26902202 DOI: 10.15252/emmm.201506106

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.

Keywords

IGF bioavailability; IGF‐binding proteins; bone; delayed growth; growth hormone.

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