Functional Characterization of a Novel HNF1A Frameshift Mutation, p.Ser471Profs*14, in an Indian Patient with MODY3 Subtype
Venkatesan RadhaAbstract
Background:
Objectives:
Since there are no functional studies of the truncation mutation, we aimed to understand the functional basis of the novel p.Ser471Profs*14 mutation in a MODY patient using different techniques.
Materials and Methods:
We had previously identified a novel frameshift variant, c.1411delT (p.Ser471Profs*14), in a 13-year-old MODY patient. Functional characterization of this mutation was done by creating the mutation using conventional site-directed mutagenesis. Transcriptional activation was performed in three cell lines. Furthermore, DNA-binding assay, Western blotting, and nuclear colocalization of the mutant were assessed along with the glucose-stimulated insulin secretion assay.
Results and Conclusion:
We identified a novel heterozygous frameshift variant, c.1411delT (p.Ser471Profs*14), in a clinically suspected MODY patient, a 13-year-old female presenting with hyperglycemia and negative pancreatic autoantibodies. The variant introduces a premature termination codon (PTC) 14 amino acids downstream of the mutation site within exon 7. As the PTC is positioned upstream of the final exon–exon junction, the mutant transcript is predicted to undergo nonsense-mediated mRNA decay, leading to haploinsufficiency. Variant interpretation classifies the variant as pathogenic. The patient demonstrated clinical responsiveness to sulfonylurea therapy, further supporting the diagnosis of pathogenicity. This study highlights the importance of combining clinical, genetic, and functional evidence for accurate interpretation of novel