Genetic analysis of the PAPP-A2 gene and evaluation of free IGF-1, IGFBP-5, and ALS concentrations in a group of 22 patients with idiopathic short stature

Endokrynol Pol. 2024;75(4):428-437. doi: 10.5603/ep.100030.

Abstract

Introduction: Short stature is one of the main reasons for consultation in outpatient clinics and paediatric endocrinology departments and is defined as height below the 3rd centile or less than -2 standard deviations (SDs).

Material and methods: The study's overarching aim was to analyse the PAPP-A2 gene at mutation sites described to date and at exons 3, 4, and 5, which encode the fragment of the catalytic domain with the active site of the pregnancy-associated plasma protein A2 (PAPP-A2) protein. The secondary aims of the study were clinical and auxological analysis of a group of patients with idiopathic short stature and biochemical analysis of growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis parameters not assessed as part of the routine diagnosis of short stature, such as free IGF-1, insulin-like growth factor binding protein 5 (IGFBP-5), and acid-labile subunit (ALS) levels. Molecular analysis of the PAPP-A2 gene was performed using polymerase chain reaction (PCR) and direct sequencing. Biochemical analysis of free IGF-1, IGFBP-5, and ALS was performed by enzyme-linked immunosorbent assay (ELISA).

Results: The mean height standard deviation score (HSDS) in the study group was -2.95. None of the patients exhibited previously described mutations in the PAPP-A2 gene or mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein. In 4 patients, the known, non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 was found.

Conclusions: Free IGF-1 levels correlate better with height and HSDS than total IGF-1 levels. The previously described mutations in the PAPP-A2 gene and mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein were not detected; only the known and non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 of the PAPP-A2 gene was observed.

Keywords: IGF-1; PAPP-A2; free IGF-1; idiopathic short stature.

MeSH terms

  • Adolescent
  • Carrier Proteins / genetics
  • Child
  • Child, Preschool
  • Female
  • Glycoproteins / blood
  • Glycoproteins / genetics
  • Growth Disorders / blood
  • Growth Disorders / genetics
  • Humans
  • Insulin-Like Growth Factor Binding Protein 5* / genetics
  • Insulin-Like Growth Factor I* / analysis
  • Insulin-Like Growth Factor I* / genetics
  • Insulin-Like Growth Factor I* / metabolism
  • Male
  • Mutation
  • Pregnancy-Associated Plasma Protein-A* / analysis
  • Pregnancy-Associated Plasma Protein-A* / genetics
  • Pregnancy-Associated Plasma Protein-A* / metabolism

Substances

  • Pregnancy-Associated Plasma Protein-A
  • Insulin-Like Growth Factor I
  • PAPPA2 protein, human
  • insulin-like growth factor binding protein, acid labile subunit
  • Insulin-Like Growth Factor Binding Protein 5
  • Carrier Proteins
  • Glycoproteins
  • IGFBP5 protein, human
  • IGF1 protein, human