Background
We assessed the response to sulfonylureas and the functional characteristics of HNF1A mutations in patients with maturity-onset diabetes of the young type 3 (MODY3).
Conclusions
The HNF1A p.Gln444fs variant associated with MODY3, and most likely a truncated protein, impaired HNF1A transcriptional activity. The variant carrier experienced an enhanced response to sulfonylureas.
Methods
We recruited a family with suspected MODY in this study, and gene sequencing (whole-exome sequencing) was used to screen germline mutations. Luciferase reporter assays were used to evaluate the activity of the mutated genes.
Results
Heterozygous HNF1A variant (NM_000545.8:c.1330_1331del, p.Gln444fs) was identified in the proband and was not found in his father, grandmother, and nonrelated healthy controls. The mutant protein had 552 amino acids, 110 fewer than the wild type protein. Furthermore, the amino acid sequence was completely different between the mutant protein and the wild type protein starting from the 444th amino acid. Luciferase reporter assays revealed that the variant had impaired HNF4A promoter-regulation activity. The patient did not achieve good hypoglycemic effects during long-term treatment with insulin and metformin. The effect of hypoglycemic treatment was highly significant after the addition of sulfonylurea drugs. Conclusions: The HNF1A p.Gln444fs variant associated with MODY3, and most likely a truncated protein, impaired HNF1A transcriptional activity. The variant carrier experienced an enhanced response to sulfonylureas.