Pathogenic monoallelic variants in GLIS3 increase type 2 diabetes risk and identify a subgroup of patients sensitive to sulfonylureas.
ACMG
Functional genetics
GLIS3
Luciferase assays
Rare variants
Type 2 diabetes
Journal
Diabetologia
ISSN: 1432-0428
Titre abrégé: Diabetologia
Pays: Germany
ID NLM: 0006777
Informations de publication
Date de publication:
05 Dec 2023
05 Dec 2023
Historique:
received:
10
07
2023
accepted:
19
09
2023
medline:
5
12
2023
pubmed:
5
12
2023
entrez:
5
12
2023
Statut:
aheadofprint
Résumé
GLIS3 encodes a transcription factor involved in pancreatic beta cell development and function. Rare pathogenic, bi-allelic mutations in GLIS3 cause syndromic neonatal diabetes whereas frequent SNPs at this locus associate with common type 2 diabetes risk. Because rare, functional variants located in other susceptibility genes for type 2 diabetes have already been shown to strongly increase individual risk for common type 2 diabetes, we aimed to investigate the contribution of rare pathogenic GLIS3 variants to type 2 diabetes. GLIS3 was sequenced in 5471 individuals from the Rare Variants Involved in Diabetes and Obesity (RaDiO) study. Variant pathogenicity was assessed following the criteria established by the American College of Medical Genetics and Genomics (ACMG). To address the pathogenic strong criterion number 3 (PS3), we conducted functional investigations of these variants using luciferase assays, focusing on capacity of GLIS family zinc finger 3 (GLIS3) to bind to and activate the INS promoter. The association between rare pathogenic or likely pathogenic (P/LP) variants and type 2 diabetes risk (and other metabolic traits) was then evaluated. A meta-analysis combining association results from RaDiO, the 52K study (43,125 individuals) and the TOPMed study (44,083 individuals) was finally performed. Through targeted resequencing of GLIS3, we identified 105 rare variants that were carried by 395 participants from RaDiO. Among them, 49 variants decreased the activation of the INS promoter. Following ACMG criteria, 18 rare variants were classified as P/LP, showing an enrichment in the last two exons compared with the remaining exons (p<5×10 Rare P/LP GLIS3 variants do contribute to type 2 diabetes risk. The variants located in the distal part of the protein could have a direct effect on its functional activity by impacting its transactivation domain, by homology with the mouse GLIS3 protein. Furthermore, rare P/LP GLIS3 variants seem to have a direct clinical effect on beta cell function, which could be improved by increasing insulin secretion via the use of sulfonylureas.
Identifiants
pubmed: 38051360
doi: 10.1007/s00125-023-06035-x
pii: 10.1007/s00125-023-06035-x
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : European Research Council
ID : 101043671
Pays : International
Informations de copyright
© 2023. The Author(s).
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