KLF11 – Maturity-onset Diabetes of the Young

KLF11 mutations have been described in small autosomal dominant pedigrees with early-onset non–ketosis-prone diabetes consistent with MODY7. A novel heterozygous variant c.31G>A (p.Asp11Asn) was identified in a three-generation family with four carriers—three with diabetes mellitus and one with impaired glucose tolerance (PMID:36874436). A second three-generation family harbored c.577C>A (p.Pro193Thr) co-segregating with diabetes in three affected relatives (PMID:36241199). Despite these reports, population-scale analyses and a recent review have questioned the penetrance and prevalence of KLF11 variants in MODY7 (PMID:36944622).

Functional studies demonstrate that KLF11 binds the insulin promoter and regulates transcription in pancreatic β-cells. Reporter assays and chromatin immunoprecipitation confirm direct KLF11‐insulin promoter interaction, and MODY7-associated variants significantly impair promoter activity and glucose-stimulated insulin secretion (PMID:15774581). Klf11 knockout mice exhibit altered insulin sensitivity but do not develop overt diabetes, supporting a dosage-sensitive role in β-cell function (PMID:26248217). Taken together, limited pedigrees and functional concordance support a possible role for KLF11 in MODY7, but incomplete penetrance and inconsistent population data warrant further study. Key take-home: KLF11 variants should be considered in MODY gene panels, with cautious interpretation given limited clinical prevalence data.

References

• World journal of clinical cases • 2023 • Novel gene mutation in maturity-onset diabetes of the young: A case report. PMID:36874436
• Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme • 2023 • Genetic and Functional Analyses of the Novel KLF11 Pro193Thr Variant in a Three-Generation Family with MODY7. PMID:36241199
• Current diabetes reviews • 2024 • Maturity-onset Diabetes of the Young Type 7 (MODY7) and the KrÃŒppellike Factor 11 Mutation (KLF11). A Review PMID:36944622
• Proceedings of the National Academy of Sciences of the United States of America • 2005 • Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. PMID:15774581
• Endocrinology • 2015 • Phenotypic Characterization of Mice Carrying Homozygous Deletion of KLF11, a Gene in Which Mutations Cause Human Neonatal and MODY VII Diabetes. PMID:26248217

Evidence Based Scoring (AI generated)