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

Abstract

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.

• Authors: Laura Di Patria, Giosuè Annibalini, Amelia Morrone, Lorenzo Ferri, Roberta Saltarelli, Luca Galluzzi, Aurora Diotallevi, Matteo Bocconcelli, Maria Alice Donati, Rita Barone, Renzo Guerrini, Jaak Jaeken, Vilberto Stocchi, Elena Barbieri
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 79 Issue 3 Pg. 150 (Feb 24 2022) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 35211808 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

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

Topics

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