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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2016-04-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201506106 |
| _version_ | 1797283997397549056 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Andrew Dauber |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T17:40:38Z |
| format | Article |
| id | doaj.art-224828b64cec4bdd98548afe1c5d47d5 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:40:38Z |
| publishDate | 2016-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-224828b64cec4bdd98548afe1c5d47d52024-03-02T16:02:51ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-04-018436337410.15252/emmm.201506106Mutations in pregnancy‐associated plasma protein A2 cause short stature due to low IGF‐I availabilityAndrew Dauber0María T Muñoz‐Calvo1Vicente Barrios2Horacio M Domené3Soren Kloverpris4Clara Serra‐Juhé5Vardhini Desikan6Jesús Pozo7Radhika Muzumdar8Gabriel Á Martos‐Moreno9Federico Hawkins10Héctor G Jasper11Cheryl A Conover12Jan Frystyk13Shoshana Yakar14Vivian Hwa15Julie A Chowen16Claus Oxvig17Ron G Rosenfeld18Luis A Pérez‐Jurado19Jesús Argente20Cincinnati Center for Growth Disorders Division of Endocrinology Cincinnati Children's Hospital Medical Center Cincinnati OH USADepartment of Pediatrics & Pediatric Endocrinology Hospital Infantil Universitario Niño Jesús Instituto de Investigación La Princesa Universidad Autónoma de Madrid Madrid SpainDepartment of Pediatrics & Pediatric Endocrinology Hospital Infantil Universitario Niño Jesús Instituto de Investigación La Princesa Universidad Autónoma de Madrid Madrid SpainCentro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE) CONICET FEI División de Endocrinología Hospital de Niños Ricardo Gutiérrez Buenos Aires ArgentinaDepartment of Molecular Biology and Genetics Aarhus University Aarhus DenmarkGenetics Unit Universitat Pompeu Fabra Hospital del Mar Research Institute (IMIM) & CIBERER. Instituto de Salud Carlos III Barcelona SpainDepartment of Pediatrics Division of Pediatric Endocrinology New York Medical College Valhalla NY USADepartment of Pediatrics & Pediatric Endocrinology Hospital Infantil Universitario Niño Jesús Instituto de Investigación La Princesa Universidad Autónoma de Madrid Madrid SpainDivision of Endocrinology Children's Hospital of Pittsburgh Pittsburgh PA USADepartment of Pediatrics & Pediatric Endocrinology Hospital Infantil Universitario Niño Jesús Instituto de Investigación La Princesa Universidad Autónoma de Madrid Madrid SpainDepartment of Endocrinology Hospital Universitario 12 de Octubre Universidad Complutense de Madrid Madrid SpainCentro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE) CONICET FEI División de Endocrinología Hospital de Niños Ricardo Gutiérrez Buenos Aires ArgentinaDivision of Endocrinology Mayo Clinic Rochester MN USAMedical Research Laboratory Department of Clinical Medicine Faculty of Health Aarhus University Aarhus DenmarkDepartment of Basic Science and Craniofacial Biology New York University College of Dentistry New York NY USACincinnati Center for Growth Disorders Division of Endocrinology Cincinnati Children's Hospital Medical Center Cincinnati OH USADepartment of Pediatrics & Pediatric Endocrinology Hospital Infantil Universitario Niño Jesús Instituto de Investigación La Princesa Universidad Autónoma de Madrid Madrid SpainDepartment of Molecular Biology and Genetics Aarhus University Aarhus DenmarkOregon Health and Science University Portland OR USAGenetics Unit Universitat Pompeu Fabra Hospital del Mar Research Institute (IMIM) & CIBERER. Instituto de Salud Carlos III Barcelona SpainDepartment of Pediatrics & Pediatric Endocrinology Hospital Infantil Universitario Niño Jesús Instituto de Investigación La Princesa Universidad Autónoma de Madrid Madrid SpainAbstract 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.https://doi.org/10.15252/emmm.201506106bonedelayed growthgrowth hormoneIGF‐binding proteinsIGF bioavailability |
| spellingShingle | 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 Mutations in pregnancy‐associated plasma protein A2 cause short stature due to low IGF‐I availability EMBO Molecular Medicine bone delayed growth growth hormone IGF‐binding proteins IGF bioavailability |
| title | Mutations in pregnancy‐associated plasma protein A2 cause short stature due to low IGF‐I availability |
| title_full | Mutations in pregnancy‐associated plasma protein A2 cause short stature due to low IGF‐I availability |
| title_fullStr | Mutations in pregnancy‐associated plasma protein A2 cause short stature due to low IGF‐I availability |
| title_full_unstemmed | Mutations in pregnancy‐associated plasma protein A2 cause short stature due to low IGF‐I availability |
| title_short | Mutations in pregnancy‐associated plasma protein A2 cause short stature due to low IGF‐I availability |
| title_sort | mutations in pregnancy associated plasma protein a2 cause short stature due to low igf i availability |
| topic | bone delayed growth growth hormone IGF‐binding proteins IGF bioavailability |
| url | https://doi.org/10.15252/emmm.201506106 |
| work_keys_str_mv | AT andrewdauber mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT mariatmunozcalvo mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT vicentebarrios mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT horaciomdomene mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT sorenkloverpris mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT claraserrajuhe mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT vardhinidesikan mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT jesuspozo mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT radhikamuzumdar mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT gabrielamartosmoreno mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT federicohawkins mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT hectorgjasper mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT cherylaconover mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT janfrystyk mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT shoshanayakar mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT vivianhwa mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT julieachowen mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT clausoxvig mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT rongrosenfeld mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT luisaperezjurado mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability AT jesusargente mutationsinpregnancyassociatedplasmaproteina2causeshortstatureduetolowigfiavailability |