title: 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 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.
authors.affiliation: Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dauber
authors.affiliation: 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.
authors.forename: María T
authors.initials: MT
authors.lastname: Muñoz-Calvo
authors.affiliation: 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.
authors.forename: Vicente
authors.initials: V
authors.lastname: Barrios
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET, FEI, División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
authors.forename: Horacio M
authors.initials: HM
authors.lastname: Domené
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Soren
authors.initials: S
authors.lastname: Kloverpris
authors.affiliation: Genetics Unit, Universitat Pompeu Fabra Hospital del Mar Research Institute (IMIM) & CIBERER. Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Serra-Juhé
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, New York Medical College, Valhalla NY, USA.
authors.forename: Vardhini
authors.initials: V
authors.lastname: Desikan
authors.affiliation: 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.
authors.forename: Jesús
authors.initials: J
authors.lastname: Pozo
authors.affiliation: Division of Endocrinology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Muzumdar
authors.affiliation: 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.
authors.forename: Gabriel Á
authors.initials: GÁ
authors.lastname: Martos-Moreno
authors.affiliation: Department of Endocrinology, Hospital Universitario 12 de Octubre Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Hawkins
authors.affiliation: Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET, FEI, División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
authors.forename: Héctor G
authors.initials: HG
authors.lastname: Jasper
authors.affiliation: Division of Endocrinology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Conover
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Frystyk
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA.
authors.forename: Shoshana
authors.initials: S
authors.lastname: Yakar
authors.affiliation: Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
authors.affiliation: 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.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Chowen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
authors.affiliation: Oregon Health and Science University, Portland, OR, USA STAT5 LLC, Los Altos, CA, USA.
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
authors.affiliation: Genetics Unit, Universitat Pompeu Fabra Hospital del Mar Research Institute (IMIM) & CIBERER. Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Pérez-Jurado
authors.affiliation: 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.
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004392:Dwarfism / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; C430889:PAPPA2 protein, human; D011266:Pregnancy-Associated Plasma Protein-A
keywords: IGF bioavailability; IGF‐binding proteins; bone; delayed growth; growth hormone