Clinical and Functional Characteristics of a Novel KLF11 Cys354Phe Variant Involved in Maturity-Onset Diabetes of the Young

Sun, Yujing; Qu, Jingru; Wang, Jing; Zhao, Ruxing; Hou, Xinguo

doi:10.1155/2021/7136869

Cited by 8 publications

(17 citation statements)

References 22 publications

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“…6,[11][12][13][14][15][16][17][18] A347S, C354F, and P307L are located in TRD3; they impair the transcriptional activity of KLF11, thus affecting the transcriptional functions of insulin in islet cells. 6,9,12,14 It has been also suggested that these mutations at this buried site are predicted to lead to its exposure on the protein surface, which consequently alters protein activity and inhibits the insulin gene promoter, leading to a decrease in insulin biosynthesis and secretion. 9,12,14 However, the mechanisms underlying this protein's activity in diabetes remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…6,9,12,14 It has been also suggested that these mutations at this buried site are predicted to lead to its exposure on the protein surface, which consequently alters protein activity and inhibits the insulin gene promoter, leading to a decrease in insulin biosynthesis and secretion. 9,12,14 However, the mechanisms underlying this protein's activity in diabetes remain unclear. Even variant and gene-level genetic evidence does not support KLF11 as the cause of MODY.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that KLF11 mutations could have incomplete penetrance and may undergo epigenetic alterations, as it has been reported that minimal promoter variants of the KLF11 gene were associated with type 2 diabetes in Japanese subjects. 8,9,12,13,20 Moreover, we cannot exclude the possibility that the maternal grandmother and the aunt of the proband had impaired insulin and C-peptide secretion because their OGTT data were unavailable.…”

Section: Discussionmentioning

confidence: 99%

“…Insulin therapy, initiated during the initial phase of MODY7, has been described previously, whereas the therapeutic effects of sulfonylureas have been reported in patients with some KLF11-MODY7 mutations. 6,12,14 In this study, both patients were treated with insulin therapy, started during the initial phase. The proband's fasting blood glucose and HbA1c levels had been poorly controlled in adolescence, while the mother's levels had been well-controlled with low-dose insulin injections and oral metformin.…”

Section: Discussionmentioning

confidence: 99%

“…These mutations in the cis ‐acting element of KLF11 inhibit KLF11‐induced activation of the insulin gene, leading to decreased insulin biosynthesis 10 . Several KLF11 mutations have been reported, including A347S, T220M, C354F, H418G, P307L, L453del, I106L, and R465H 6,11–18 . A347S, C354F, and P307L are located in TRD3; they impair the transcriptional activity of KLF11, thus affecting the transcriptional functions of insulin in islet cells 6,9,12,14 .…”

Section: Discussionmentioning

confidence: 99%

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A novel KLF11 variant in a family with maturity‐onset diabetes of the young

Zhang

Liu

et al. 2022

Pediatric Diabetes

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Objective: The Krüppel-like factor 11 (KLF11) gene causes maturity-onset diabetes of the young 7 (MODY7). There are few reports on the clinical and functional characteristics of KLF11 mutations in patients with MODY7, making diagnosis and treatment complicated.Research Design and Methods: We report a novel KLF11 variant associated with MODY7 in a Chinese family. The proband had hyperglycemia at 9 years of age, and his mother had developed diabetes at age 28 years. Both required insulin injections from the initial phase of the disease. They were negative for islet cell autoantibodies and had normal fasting C-peptide levels. We observed changes in the levels of fasting blood glucose, C-peptide, and islet cell autoantibodies in the proband over 4.5 years.Results: Whole-exon sequencing was used to screen the proband and his family members for KLF11 variants. The heterozygous KLF11 variant (c.1045C>T, p. Pro349Ser) was identified in the proband, his mother, his maternal grandmother, and an elderly aunt, although the latter two individuals were unaffected. In silico analyses indicated that this variant involved a change in the amino acid side chain in the transcriptional regulatory domain 3. Luciferase reporter assays revealed that the variant had impaired insulin promoter regulation activity. Moreover, in vitro analyses showed that this variant impaired insulin secretion from pancreatic beta cells.Conclusions: This study documents a novel heterozygous KLF11 variant (p. Pro349Ser) as a potential monogenic mutation associated with MODY7 in a family. This variant impairs insulin secretion from pancreatic beta cells, possibly by repressing insulin promoter regulation activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A novel KLF11 variant in a family with maturity‐onset diabetes of the young

Zhang

Liu

et al. 2022

Pediatric Diabetes

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Genetic and Functional Analyses of the Novel KLF11 Pro193Thr Variant in a Three-Generation Family with MODY7

et al. 2022

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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.577C>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.

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