Defective IGF-1 prohormone N-glycosylation and reduced IGF-1 receptor signaling activation in congenital disorders of glycosylation.
Biomarkers
/ metabolism
Congenital Disorders of Glycosylation
/ metabolism
Endoplasmic Reticulum Stress
Fibroblasts
/ metabolism
Gene Expression Regulation
Humans
Insulin-Like Growth Factor I
/ metabolism
Lectins
/ metabolism
Phosphorylation
RNA, Messenger
/ genetics
Receptor, IGF Type 1
/ metabolism
Signal Transduction
IGF-1 deficiency
IGF-1/IGF-1R signaling pathway
Lectins
Metabolic disorders
N-linked glycosylation
Rare genetic disease
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
24 Feb 2022
24 Feb 2022
Historique:
received:
14
10
2021
accepted:
31
01
2022
revised:
24
01
2022
entrez:
25
2
2022
pubmed:
26
2
2022
medline:
3
3
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35211808
doi: 10.1007/s00018-022-04180-x
pii: 10.1007/s00018-022-04180-x
pmc: PMC8873121
doi:
Substances chimiques
Biomarkers
0
Lectins
0
RNA, Messenger
0
Insulin-Like Growth Factor I
67763-96-6
Receptor, IGF Type 1
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
150Informations de copyright
© 2022. The Author(s).
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