Genotype-Phenotype Discrepancies in Family Members With a Novel Glucokinase Mutation: Insights Into GCK-MODY and Its Interplay With Insulin Resistance

Abstract

Heterozygous inactivating mutations in the glucokinase (GCK) gene cause maturity-onset diabetes of the young (GCK-MODY). We identified a novel variant of uncertain significance in the GCK gene (c.77A>T, p.Q26L) in two family members exhibiting contrasting diabetic phenotypes. To explore the diabetogenic potential of the GCK-Q26L mutation and investigate the mono- and polygenetic factors contributing to different phenotypes, whole-exome sequencing and polygenic risk score (PRS) assessments were conducted on three family members. We found that the proband inherited the GCK-Q26L mutation from her father (who had mild, stable hyperglycemia) but exhibited more severe diabetic symptoms, including polydipsia, polyuria, weight loss, ketosis, and significant dyslipidemia. Genetic analysis linked the proband’s severe phenotypes to her high PRS for insulin resistance (IR) and type 2 diabetes. A global knock-in mouse model expressing GCK-Q26L presented mild hyperglycemia, impaired glucose tolerance, reduced serum insulin, and impaired glucose-stimulated insulin secretion. Both dorzagliatin and liraglutide improved glucose tolerance and insulin secretion in mutant mice. This study demonstrates that GCK-Q26L is a pathogenic GCK-MODY mutation, and its associated phenotypes are influenced by PRS for IR and type 2 diabetes. Article Highlights This study was undertaken to investigate the diabetogenic potential of a novel GCK variant, c.77A>T, p.Q26L, found in two family members with marked differences in diabetic phenotypes. We aimed to understand the role of GCK-Q26L in glucose metabolism and to explore whether genetic backgrounds, including polygenic risk score for insulin resistance and type 2 diabetes, contribute to diabetes manifestations. We found that GCK-Q26L is a pathogenic mutation leading to GCK-MODY, with severity modulated by polygenic risk score for insulin resistance and type 2 diabetes. These findings not only expand the list of GCK-MODY causing mutations but also highlight the importance of polygenic backgrounds in the clinical presentation and management of monogenic diabetes.