Abstract
KLF11 regulates insulin gene expression through binding to the insulin promoter
and has been reported as a causative gene for maturity-onset diabetes of the
young 7 (MODY7). Here, we report a novel KLF11 variant associated with a
three-generation family with early childhood-onset diabetes and explore its
clinical and functional characteristics. The three-generational pedigree
contains five patients affected by diabetes. The pathogenic variant identified
by whole-exome sequencing was further confirmed by Sanger sequencing and
pedigree verification. Luciferase reporter assays and glucose-stimulated insulin
secretion were used to examine whether the KLF11 variant binds to the insulin
promoter and regulate insulin secretion in vitro. The proband, his son, and his
uncle exhibited hyperglycemia at ages 32, 13 and 71 years, respectively. All
three patients showed characteristics of metabolic syndrome (obesity,
dyslipidemia, and diabetes), but the insulin secretion of islet β-cells
was impaired. A novel heterozygous missense variant, c.577 C>A
(p.Pro193Thr) of the KLF11 gene was detected in all three patients. This variant
co-segregates with the diabetes phenotype, consistent with an autosomal dominant
disorder. The identified KLF11 p.Pro193Thr variant drastically decreased the
transcriptional activity of KLF11, as demonstrated by luciferase reporter assay.
Functional analyses revealed that the KLF11 Pro193Thr variant inhibited
glucose-stimulated insulin secretion. We identified a novel KLF11 Pro193Thr
variant in a three generation family with MODY7. These findings shed light on
the molecular mechanisms underlying the pathogenesis of MODY7 and expand the
genotype and clinical spectrum of MODY7.
Key words
maturity-onset diabetes of the young 7 - KLF11 - variant
