KLF11 – Monogenic Diabetes

KLF11 encodes a pancreas-enriched Kruppel-like transcription factor critical for insulin gene regulation. Heterozygous pathogenic variants in KLF11 cause maturity-onset diabetes of the young subtype 7 (MODY7), an autosomal dominant form of monogenic diabetes characterized by early-onset hyperglycemia and insulin deficiency. Clinical recognition of MODY7 informs personalized management and genetic counseling.

Several independent families harbor distinct KLF11 missense variants segregating with MODY7. A three-generation pedigree with five affected individuals was found to carry c.577C>A (p.Pro193Thr) (PMID:36241199). In a separate family, c.1061G>T (p.Cys354Phe) was identified in three affected relatives spanning three generations (PMID:33604390). A third kindred exhibited c.1045C>T (p.Pro349Ser) co-segregating with diabetes in two members (PMID:35689450). These reports encompass three probands and seven additional affected relatives, confirming autosomal dominant inheritance.

All reported variants are rare heterozygous missense changes localized within the transcriptional regulatory domains of KLF11. No recurrent or founder alleles have been described. In silico predictions and absence from population databases support pathogenicity. The variant spectrum underscores the need for full‐gene sequencing in suspected MODY cases.

Functional assays consistently demonstrate impaired KLF11 activity. Luciferase reporter studies show that p.Pro193Thr and p.Cys354Phe dramatically reduce insulin promoter activation and blunt glucose-stimulated insulin secretion in β-cell lines (PMID:36241199; PMID:33604390). The p.Pro349Ser change similarly impairs transactivation of a GC-box–containing proinsulin promoter (PMID:35689450).

Mechanistically, KLF11 functions as a glucose-inducible transcriptional activator of INS; pathogenic variants exert haploinsufficiency or dominant-negative effects on insulin gene expression. These findings align with the clinical phenotype of reduced insulin secretion and early-onset diabetes in affected individuals.

Integration of genetic and functional data yields a Strong level of clinical validity for KLF11 in monogenic diabetes (MODY7). Recommendation: include KLF11 in diagnostic gene panels for monogenic diabetes, especially in autoantibody-negative patients with preserved C-peptide. Key Take-home: Pathogenic heterozygous variants in KLF11 are a definitive cause of autosomal dominant monogenic diabetes (MODY7), and their identification guides precise treatment and familial screening.

References

• Hormone and metabolic research • 2023 • Genetic and Functional Analyses of the Novel KLF11 Pro193Thr Variant in a Three-Generation Family with MODY7 PMID:36241199
• Journal of diabetes research • 2021 • Clinical and Functional Characteristics of a Novel KLF11 Cys354Phe Variant Involved in Maturity-Onset Diabetes of the Young PMID:33604390
• Pediatric diabetes • 2022 • A novel KLF11 variant in a family with maturity-onset diabetes of the young PMID:35689450

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