Defective IGF-1 prohormone N-glycosylation and reduced IGF-1 receptor signaling activation in congenital disorders of glycosylation

Cell Mol Life Sci. 2022 Feb 24;79(3):150. doi: 10.1007/s00018-022-04180-x.


The insulin-like growth factor-1 (IGF-1) signaling pathway is crucial for the regulation of growth and development. The correct processing of the IGF-1Ea prohormone (proIGF-1Ea) and the IGF-1 receptor (IGF-1R) peptide precursor requires proper N-glycosylation. Deficiencies of N-linked glycosylation lead to a clinically heterogeneous group of inherited diseases called Congenital Disorders of Glycosylation (CDG). The impact of N-glycosylation defects on IGF-1/IGF-1R signaling components is largely unknown. In this study, using dermal fibroblasts from patients with different CDG [PMM2-CDG (n = 7); ALG3-CDG (n = 2); ALG8-CDG (n = 1); GMPPB-CDG (n = 1)], we analyzed the glycosylation pattern of the proIGF-1Ea, IGF-1 secretion efficiency and IGF-1R signaling activity. ALG3-CDG, ALG8-CDG, GMPPB-CDG and some PMM2-CDG fibroblasts showed hypoglycosylation of the proIGF-1Ea and lower IGF-1 secretion when compared with control (CTR). Lower IGF-1 serum concentration was observed in ALG3-CDG, ALG8-CDG and in some patients with PMM2-CDG, supporting our in vitro data. Furthermore, reduced IGF-1R expression level was observed in ALG3-CDG, ALG8-CDG and in some PMM2-CDG fibroblasts. IGF-1-induced IGF-1R activation was lower in most PMM2-CDG fibroblasts and was associated with decreased ERK1/2 phosphorylation as compared to CTR. In general, CDG fibroblasts showed a slight upregulation of Endoplasmic Reticulum (ER) stress genes compared with CTR, uncovering mild ER stress in CDG cells. ER-stress-related gene expression negatively correlated with fibroblasts IGF-1 secretion. This study provides new evidence of a direct link between N-glycosylation defects found in CDG and the impairment of IGF-1/IGF-1R signaling components. Further studies are warranted to determine the clinical consequences of reduced systemic IGF-1 availability and local activity in patients with CDG.

Keywords: IGF-1 deficiency; IGF-1/IGF-1R signaling pathway; Lectins; Metabolic disorders; N-linked glycosylation; Rare genetic disease.

MeSH terms

  • Biomarkers / metabolism
  • Congenital Disorders of Glycosylation / metabolism*
  • Endoplasmic Reticulum Stress
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression Regulation
  • Humans
  • Insulin-Like Growth Factor I / metabolism*
  • Lectins / metabolism
  • Phosphorylation
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction*


  • Biomarkers
  • Lectins
  • RNA, Messenger
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1