# Clinical and functional characteristics of the KLF11 (p.R29Q) variant associated with MODY7

## TL;DR

This study examines the KLF11 R29Q mutation linked to MODY7 diabetes, showing how it affects insulin regulation and secretion in patients.

## Contribution

The study provides new clinical and functional insights into the KLF11 R29Q variant's role in MODY7.

## Key findings

- The KLF11 R29Q variant impairs insulin promoter regulatory activity in pancreatic β-cells.
- The mutation disrupts KLF11 protein structure and stability, reducing insulin expression and secretion.
- Clinical cases show variable disease severity and treatment responses among carriers of the KLF11 R29Q variant.

## Abstract

The KLF11 gene can cause maturity-onset diabetes of the young type 7 (MODY7). Currently, there are few reports on MODY7 cases and their clinical and functional characteristics. This study aimed to analyze the clinical and functional features of the KLF11 R29Q variant to provide a basis for the diagnosis and treatment of this disease.

Clinical baseline data of patients were collected, and high−throughput sequencing (NGS) was used to screen probands clinically suspected of harboring KLF11 variants, with validation performed in their family members. A luciferase reporter assay was used to test whether the KLF11 R29Q variant binds to the insulin promoter. Real-time PCR, western blotting, and glucose-stimulated insulin secretion (GSIS) assays were employed to analyze insulin expression and insulin secretion activity in β-cell lines.

1) Clinical data showed that Proband 1 presented with insulin dependence, severe hyperlipidemia, diabetic retinopathy, and cataract at the initial stage of the disease. A relatively high dose of insulin was required and could not be completely discontinued; after insulin treatment, glucose and lipid metabolic disorders and visual acuity were improved. Proband 2 exhibited poor islet function at early onset, accompanied by diabetic autonomic neuropathy and peripheral neuropathy, and glycemic control remained unsatisfactory despite insulin therapy. 2) Genetic testing demonstrated that the heterozygous KLF11 R29Q variant was identified in Proband 1, her father, and her elder sister, as well as in Proband 2 and her mother. The elder sister of Proband 1 was in a prediabetic state, whereas this variant was not detected in Proband 1’s mother or younger brother. The mother of Proband 2 had normal blood glucose levels and displayed no diabetes-related clinical manifestations. 3) Protein three-dimensional structure predictions indicated that the KLF11 R29Q mutation affects the electrostatic potential on the surface of the KLF11 protein molecule, disrupting its tertiary structure and compromising protein stability. 4) Cell-based luciferase reporter assays using wild-type and mutant constructs demonstrated that the KLF11 R29Q variant had impaired insulin promoter regulatory activity. Furthermore, real-time PCR, western blotting, and GSIS analyses indicated that this variant impairs insulin expression in pancreatic β-cells and inhibits insulin secretion.

We studied a KLF11 R29Q single-gene mutation associated with MODY7. The study confirmed that this variant has impaired insulin promoter regulatory activity and inhibits insulin expression and secretion.