Digenic HNF1A and ABCC8 variants provide mechanistic insight into early-onset diabetes
Abstract
Context: Oligogenic inheritance in maturity-onset diabetes of the young (MODY) remains poorly characterized, and the contribution of multiple candidate variants to disease pathogenesis is incompletely understood.
Objective: To investigate the pathogenicity and mechanistic contribution of multiple MODY gene variants identified in a MODY-like family and determine their role in early-onset diabetes.
Methods: Comprehensive genetic analysis of known MODY genes was performed in a MODY-like family. Functional effects of HNF1A and HNF1B variants were assessed using luciferase reporter assays in HEK293T cells. Functional characterization of ABCC8 variants included Kir6.2-dependent thallium (Tl+) flux assays, sulfonylurea responsiveness, and channel stability.
Results: Four variants in 3 MODY genes were identified in the proband: novel HNF1A p.Ser551Lysfs*2, HNF1B p.Glu102Ala, and ABCC8 p.Arg298Cys and p.Arg521Gln. Functional analysis showed that HNF1A p.Ser551Lysfs*2 retained approximately 5% of wild-type transactivation activity, consistent with loss-of-function, whereas HNF1B p.Glu102Ala and ABCC8 p.Arg521Gln exhibited wild-type-like function. In contrast, ABCC8 p.Arg298Cys reduced channel activity to 77% of wild-type levels while preserving sulfonylurea responsiveness. Segregation analysis identified HNF1A p.Ser551Lysfs*2 and ABCC8 p.Arg298Cys in affected parents. The proband, who inherited both pathogenic variants, developed diabetes earlier than either parent and was exposed to…
How strong is the evidence?
Evidence Hub reads this as a case report, done in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
Read the paper
Related studies
- The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity
- Hypoglycemic medicines in the treatment of Alzheimer’s disease: Pathophysiological links between AD and glucose metabolism
- Isorhamnetin Reduces Glucose Level, Inflammation, and Oxidative Stress in High-Fat Diet/Streptozotocin Diabetic Mice Model
- Modulating Sirtuin Biology and Nicotinamide Adenine Diphosphate Metabolism in Cardiovascular Disease—From Bench to Bedside
- Characterization of the SGLT2 Interaction Network and Its Regulation by SGLT2 Inhibitors: A Bioinformatic Analysis
- Early Treatment with Empagliflozin and GABA Improves β-Cell Mass and Glucose Tolerance in Streptozotocin-Treated Mice
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.