1821-P: Coinheritance of HNF1A and Glucokinase Variants in Diabetes—Implications for Functional Assay

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Introduction and Objective: The classification of maturity-onset diabetes of the young (MODY) pertains to monogenic forms of diabetes possessing an autosomal dominant mode of inheritance. The two most commonly seen subtypes are MODY2 and MODY3, caused by loss of function variants in the Glucokinase (GCK) and HNF1A genes, respectively. Our patient is an 18-year-old Caucasian male with a ten-year history of elevated fasting blood glucose. Work up revealed 106 mg/dL of fasting glucose, 6.0% glycated hemoglobin (HbA1C), normal C-peptide, and negative seropositivity for pancreatic islet autoantibodies. Genetic analysis identified two missense alleles: a pathogenic variant of GCK (c.1364T>A, p.Val455Glu) and a variant of HNF1A (c.1610C>T, p.Thr537Met) considered to be of uncertain significance (VUS). Since MODY2 does not require treatment, determining the HNF-1α T537M variant’s pathogenicity is of critical importance for informing clinical decisions.Methods: WT and T537M HNF-1α constructs were co-transfected with a luciferase construct carrying the mouse hepatocyte growth factor activator (Hgfac) gene promoter. Nuclear localization and protein expression levels were evaluated with immunoblotting after isolating the nuclear and cytosol fractions.Results: Compared with the WT, the T537M mutant showed markedly reduced transactivation in both MIN6 cells (with endogenous HNF-1α) and Hela cells (without endogenous HNF-1α). Neither nuclear localization nor protein levels of the HNF-1α T537M mutant differed significantly from the WT.Conclusion: The HNF1A variant c.1610C>T, which results in an amino acid substitution of methionine for threonine at position p.137 and was initially classified as a VUS, is likely pathogenic. The patient should be closely monitored. It should also be noted in this case that the baseline target for diabetes control has been elevated due to co-inheritance of a GCK mutation.

Disclosure

J.Q. Dai-Ju: None. A. Idriss: None. Y. Cao: None. K. Yamagata: None. Q. Yang: None.

Funding

National Institutes of Diabetes and Digestive and Kidney Diseases(3R01DK136940-02S1); UCI School of Medicine (Dean’s K Scholar); UCI School of Medicine (Department of Medicine Chair Research Award)



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