Novel Kruppel-like factor 11 variant of maturity-onset diabetes of the young type 7: A case report

Abstract

BACKGROUND

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes often misdiagnosed as type 1 or type 2. The MODY7 subtype, attributed to variants in the Kruppel-like factor 11 (KLF11) gene, is exceedingly rare, and its clinical spectrum is not fully characterized. Precise genetic diagnosis is essential for appropriate management but is challenging due to phenotypic overlap with other diabetes types. This case report describes a patient with a novel KLF11 variant, contributing to the understanding of this rare condition and its clinical implications.

CASE SUMMARY

A 50-year-old female with a family history of MODY in her son was initially diagnosed with type 2 diabetes. Due to the family history and a non-obese phenotype, a comprehensive genetic panel for monogenic diabetes was performed. The analysis identified a novel heterozygous missense variant, p.Cys105Phe, in the KLF11 gene, establishing a definitive diagnosis of MODY7. Following this diagnosis, the patient’s treatment was adjusted to include lifestyle modifications, resulting in adequate glycemic control. The patient has since maintained target glycated hemoglobin levels.

CONCLUSION

Monogenic diabetes type MODY7, caused by a mutation in the KLF11 gene, is extremely rare. Although some studies question its existence, compatible cases continue to be diagnosed, given its inclusion in genetic panels for MODY.

Key Words: Maturity-onset diabetes of the young type 7; Kruppel-like factor 11; Diabetes mellitus; Gene mutation; Case report

Core Tip: Maturity-onset diabetes of the young (MODY), accounting for 1%-5% of all diabetes cases, is a genetic disorder with subtypes defined by specific gene variants. MODY type 7, a rare form (less than 1% of MODY cases), is linked to the KLF11 gene. We report a MODY type 7 case caused by a novel variant (p.Cys105Phe) in Kruppel-like factor 11. Given its low prevalence and overlap with other diabetes types, precise genetic diagnosis is crucial for confirmation, understanding clinical implications, and optimizing patient care.

INTRODUCTION

Monogenic diabetes, known as maturity-onset diabetes of the young (MODY), is a group of genetic disorders with an autosomal dominant inheritance pattern. It typically manifests at an early age and accounts for approximately 1%-5% of all diabetes cases. Each MODY subtype is associated with a specific mutation in a particular gene, primarily described for subtypes 1-6. MODY type 7 (MODY7) is one of the subtypes in which the Kruppel-like factor 11 (KLF11) is identified as a genetic predisposition, and its worldwide prevalence among MODY cases is less than 1%[1,2].

MODY is defined by a set of clinical and genetic criteria that distinguish it from other forms of diabetes. The condition is typically characterized by an early onset of hyperglycemia, often diagnosed before the age of 25 years in at least one affected family member. A positive family history spanning at least two generations is generally present, supporting an autosomal dominant inheritance pattern. A key feature of MODY is the preservation of endogenous insulin secretion, demonstrated by insulin independence for a minimum of three years post-diagnosis and/or a C-peptide level exceeding 200 pmol/L. Additionally, affected individuals show a consistent absence of pancreatic islet autoantibodies, which helps differentiate MODY from autoimmune diabetes. Definitive diagnosis requires the identification of a pathogenic variant through genetic testing, consistent with one of the known MODY-associated genes[3].

KLF11 is a member of the Kruppel-like factor family, which belongs to a group of zinc finger transcription factors. This gene can bind to different factors to exert various functions in transcriptional regulation. In pancreatic β-cells, KLF11 acts as a regulator by inhibiting the activity of the insulin gene promoter, leading to a decrease in cell proliferation and an increase in apoptosis. Specifically, the insulin gene promoter region is responsible for increased insulin levels, and its alteration results in decreased insulin biosynthesis and subsequent elevation of blood glucose levels[4].

Building on this, KLF11 encodes a transcription factor of the KLF/Sp1 family, broadly expressed in human tissues and notably active in pancreatic islet cells, where it plays a regulatory role in insulin gene expression. It functions by binding to GC-rich sequences in the promoter regions of target genes, suppressing their transcription. Structurally, KLF11 contains three Cys2His2-type zinc finger domains responsible for DNA binding and three transcriptional repressor domains that mediate interactions with regulatory cofactors. Functional studies, including KLF11 knockout mouse models, have demonstrated that disruption of KLF11 Leads to reduced serum insulin levels, supporting its critical role in modulating insulin synthesis and secretion[5,6]. Variants in KLF11 may therefore impair insulin gene regulation by altering DNA-binding capacity, disrupting repressor domain interactions, or reducing transcriptional activity at insulin promoter regions[5,6].

In 2005, Neve et al[7] published the first report on KLF11, identifying two variants (Ala347Ser and Thr220Met) in families with early-onset type 2 diabetes. Since then, additional variants have been described, including Pro193Thr, Gln62Arg, c.G31A, p.His418Gln, Cys354Phe, and others described in Table 1[6-13]. In this study, we present a case of a patient harboring a mutation in the KLF11 gene associated with MODY7, which is linked to a variant not previously described in the literature (p.Cys105Phe). This specific variant was identified through comprehensive genetic analysis and is deemed significant for the clinical presentation and diagnosis of MODY7.

Table 1 Reported maturity-onset diabetes of the young type 7 cases and associated Kruppel-like factor 11 variants.

Ref.	KLF11 mutation	Amino acid change	Clinical phenotype	Penetrance/notes
Wang et al[11], 2024	c.820C>T	p.Pro274Ser (P274S)	Diabetes mellitus in 2 individuals; hyperinsulinemia in 1 family member	Autosomal dominant inheritance; managed with insulin, acarbose, and oral antidiabetic agents
Song et al[12], 2024	c.793G>A	p.Glu265 Lys (E265K)	Diabetes in 30-year-old male; non-diabetic carrier mother	Suggests incomplete penetrance; raises doubts about clinical relevance of KLF11 in MODY panels
Zhang et al[9], 2023	c.31G>A	p.Asp11Asn (D11N)	Diabetes in 3 family members; impaired glucose tolerance in 1 individual	Confirmed by next-generation sequencing; blood glucose controlled with metformin and dietary intervention
Guan et al[8], 2023	c.193C>A	p.Pro193Thr (P193T)	MODY7 in a three-generation pedigree	Impaired insulin secretion due to disrupted promoter activity; functional impact confirmed in vitro
Wu et al[13], 2022	c.1045C>T	p.Pro349Ser (P349S)	Index patient with diabetes; several non-diabetic relatives carrying the variant	Detected in three generations; incomplete penetrance suggests possible epigenetic or environmental modulation
Sun et al[10], 2021	c.1061G>T	p.Cys354Phe (C354F)	Diabetes at age 23; prediabetes in mother; T2DM in grandfather	Reduced insulin transcription and secretion; functional impairment confirmed in vitro; improved control with sulfonylureas and diet
Ushijima et al[6], 2019	Not codified precisely	p.His418Gln (H418Q)	Early-onset type 1B diabetes (age 1-4); insulin-dependent from diagnosis	Dominant-negative effect; negative for islet autoantibodies; altered transcriptional repression of insulin gene
Neve et al[7], 2005	Various; e.g., c.185A>G	p.Gln62Arg (Q62R)	Multifactorial T2DM; case-control and family studies	Three missense variants associated with early-onset T2DM; functional impairment of βcell proliferation and insulin secretion

KLF11: Kruppel-like factor 11; MODY7: Maturity-onset diabetes of the young type 7; T2DM: Type 2 diabetes mellitus.

CASE PRESENTATION

Chief complaints

A 50-year-old female patient presented to the endocrinology clinic for a follow-up evaluation regarding her diagnosis of diabetes mellitus. who was diagnosed at the age of 48. Initially, diagnostic criteria from the American Diabetes Association were used, including glycated hemoglobin (HbA1c) > 6.5% and fasting glucose > 126 mg/dL (admission with HbA1c levels of 7.6% and fasting glucose of 132 mg/dL).

History of present illness

The patient presented to the endocrinology clinic with a diagnosis of type 2 diabetes mellitus, which was made two years prior. However, her pharmacological treatment had been irregular, and she was not currently taking any hypoglycemic medications. Her HbA1c levels were persistently in the diabetic range of 6.5% to 7.0%. This, along with her family history, drew the attention of the medical staff.

History of past illness

Her medical history was significant for overweight, well-controlled hypertension on amlodipine and valsartan, and type 2 diabetes mellitus diagnosed at age 48. She was not taking any hypoglycemic medications at the time of evaluation.

Personal and family history

Family history revealed a 15-year-old son diagnosed with MODY7, carrying a heterozygous mutation in the KLF11 gene (specifically, the c.314G variant). He had not required pharmacological treatment, and his diabetes remains under good metabolic control. Data on his laboratory studies, including C-peptide and pancreatic antibodies, are currently unavailable. A daughter also carries the same mutation and was evaluated for episodes of non-fasting hypoglycemia, without the presence of Whipple’s triad; however, she had not yet met the criteria for diabetes.

Physical examination

The physical examination was unremarkable.

Laboratory examinations

Laboratory examinations upon admission revealed an HbA1c of 7.6% and a fasting glucose of 132 mg/dL, both of which were above the diagnostic thresholds for diabetes (> 6.5 mg/L and > 126 mg/dL, respectively). Autoimmunity was ruled out based on the absence of antibodies against insulin, islet cells, and glutamic acid decarboxylase, and C-peptide levels were within the normal range (Table 2). Genetic analysis was performed using next-generation sequencing, which identified the KLF11 gene mutation c.314G>T (p.Cys105Phe) variant. The clinical significance of this variant is currently uncertain.

Table 2 Paraclinical studies of the patient with diabetes maturity-onset diabetes of the young type.

Clinical laboratories	Results	Reference values (adults, conventional units)
Glycosylated hemoglobin	6.8%	4.0%-5.6% (normal); 5.7%-6.4% (prediabetes); ≥ 6.5% (diabetes)
Creatinine	0.97 mg/dL	0.6-1.3 mg/dL (women: 0.6-1.1 mg/dL, men: 0.7-1.3 mg/dL)
Urea nitrogen	24.3 mg/dL	7-20 mg/dL
Total cholesterol	181 mg/dL	< 200 mg/dL (desirable); 200-239 mg/dL (borderline); ≥ 240 mg/dL (high)
LDL cholesterol	95.6 mg/dL	< 100 mg/dL (optimal); 100-129 mg/dL (near optimal); ≥ 130 mg/dL (elevated)
HDL cholesterol	60 mg/dL	> 40 mg/dL (men); > 50 mg/dL (women); ≥ 60 mg/dL (cardioprotective)
Ionic calcium	1.3 mmol/L	1.12-1.32 mmol/L
C-peptide	3.48 ng/mL	0.8-3.1 ng/mL (fasting)
Anti-insulin, anti-islet, anti-GAD antibodies	Negative	Anti-insulin antibodies, negative, < 0.4 U/mL. Islet cell antibodies, negative, titer < 1:4; Anti-GAD antibodies, negative, < 5 U/mL

LDL: Low-density lipoprotein; HDL: High-density lipoprotein; GAD: Glutamic acid decarboxylase.

Imaging examinations

There was no imaging examination.

FINAL DIAGNOSIS

Given the clinical course of the disease, the autosomal dominant pattern, and the first-degree family history, MODY diabetes was suspected, prompting a genetic panel that reported the KLF11 gene mutation c.314G>T (p.Cys105Phe) variant, consistent with MODY7. Genetic analysis was performed using next-generation sequencing.

TREATMENT

Following genetic confirmation and during management with intensified lifestyle changes, the patient remained stable with follow-up HbA1c levels (average 6.6%) and good glycemic control.

OUTCOME AND FOLLOW-UP

After 3 years the patient continues to be monitored and managed through a healthy lifestyle approach, and her metabolic control remains stable.

DISCUSSION

The case of a 50-year-old woman, diagnosed with type 2 diabetes at age 48, meets several clinical criteria for MODY. Although her age at diagnosis exceeds the typical threshold, her 15-year-old son was diagnosed with MODY7, and her daughter, who carries the same KLF11 variant (c.314G>T, p.Cys105Phe), shows hypoglycemia without diabetes - supporting a multigenerational, autosomal dominant pattern. The patient maintains stable glycemic control (HbA1c 6%-7%) without insulin or pharmacologic therapy, and her preserved C-peptide levels indicate endogenous insulin production[3].

Autoimmune causes were ruled out through negative anti-glutamic acid decarboxylase, anti-insulin, and anti-islet antibodies. Genetic testing revealed the same heterozygous KLF11 variant in Exon 3, also found in her children. While this variant is currently classified as of uncertain clinical significance, its familial segregation and the absence of beta-cell failure support a MODY7 diagnosis. MODY should be suspected in patients with atypical features of type 1 diabetes mellitus and type 2 diabetes mellitus, such as the absence of autoimmunity against pancreatic islets, normal C-peptide levels, and low insulin requirements (atypical features compared to type 1 diabetes mellitus). In addition, early onset before the age of 45 years, absence of overweight/obesity and absence of signs of insulin resistance (atypical features compared to type 2 diabetes mellitus) should raise suspicion[2,7,14].

The diagnosis of MODY poses a clinical challenge due to its low prevalence and overlap with other types of diabetes in terms of presentation and clinical features. Distinctive features of MODY include an autosomal dominant inheritance pattern, multigenerational family history of diabetes, and onset before the age of 25 years, along with the absence of autoimmunity and/or insulin resistance. These criteria were proposed in 2008 as part of the diagnostic criteria[2,3]. The diagnosis of MODY has implications for treatment, follow-up, and identification of other affected family members. Standard treatments have not been established for most MODY subtypes due to the low number of cases and limited evidence available[15]. Some MODY subtypes present with mild hyperglycemia, which can be controlled by dietary changes.

Descriptive studies have shown adequate glycemic control with oral antidiabetics, especially sulfonylureas, indicated mainly in the most frequent subtypes such as hepatocyte nuclear factor 1 homeobox A, hepatocyte nuclear factor-4 alpha, PDX1, hepatocyte nuclear factor 1 beta and neurogenic differentiation 1[1]. However, the use of other drugs such as glucagon-like peptide-1 receptor agonists has been little reported; Broome et al[2] documented their efficacy in a patient with cardiovascular risk, supporting their use by the benefit demonstrated in the reduction of morbidity and mortality in type 2 diabetes. In the case of MODY7, early use of insulin, as well as biguanides and sulfonylureas, has been described. It has also been reported that dietary intervention can contribute to glycemic control in patients with KLF11 mutations, as evidenced in our case[6,9,10].

Recently, this possible correlation has been questioned, suggesting the need for more comprehensive diagnostic approaches. In this line, studies such as that of Laver et al[16] have raised a critical review of the role of certain genes in the etiology of MODY. In their analysis, they conclude that genetic evidence at the variant and gene level does not support BLK, KLF11 or PAX4 as a cause of MODY, and recommend that they should not be included in diagnostic genetic testing for MODY. This approach calls into question the routine inclusion of KLF11 in diagnostic panels, opening a debate about the validity and penetrance of its variants. However, in contrast to these findings, other recent studies support the pathogenic role of KLF11 mutations in certain clinical and familial contexts. For example, Wang et al[11] reported a case where three members of the same family had heterozygous mutations in the KLF11 gene (c.820C>T, p.P274S). Of these, two patients developed diabetes mellitus, while another presented hyperinsulinemia, suggesting a phenotypic spectrum associated with the same genetic alteration.

Additionally, the article published by Ushijima et al[6] provides functional evidence by demonstrating that KLF11 regulates insulin gene expression by binding to the GC sequence in its promoter. In their study, they describe a new variant associated with early childhood-onset type 1B diabetes. The case included the patient and his sister, who presented with hyperglycemia before the first year of life, and his mother, who was diagnosed at age 4 years. This familial pattern supports the hypothesis that specific KLF11 variants with dominant-negative effect may be responsible for early and atypical forms of diabetes, thus consolidating its possible role within the MODY spectrum.

The novel variant reported by Ushijima et al[6], p.His418Gln, directly addresses the concerns raised by Laver et al[16] regarding the pathogenic relevance of KLF11 in MODY7. This study provides strong functional evidence of a dominant-negative effect of the variant, which abolishes the repressor activity of wild-type KLF11 on the insulin promoter in luciferase assays. Moreover, the variant segregates in a family with early-onset, insulin-dependent diabetes negative for islet autoantibodies, a profile consistent with monogenic diabetes. Therefore, these findings support the biological plausibility and clinical significance of specific KLF11 mutations and argue against the exclusion of KLF11 from diagnostic panels. In this sense, they highlight the importance of variant-level analysis and functional validation to refine gene inclusion criteria in MODY testing. Furthermore, studies with a larger population, such as a Turkish pediatric cohort studied by Özsu et al[17], identified KLF11 variants in 3.6% of patients with a genetic diagnosis of MODY - a proportion similar to that of hepatocyte nuclear factor 4 alpha - which reinforces its clinical relevance. This observation aligns with previously mentioned reports describing familial cases with KLF11 mutations associated with diabetes or alterations in insulin secretion, thereby underscoring the gene’s continued value in diagnostic and research contexts.

CONCLUSION

In conclusion, this case illustrates the relevance of considering MODY in adult-onset diabetes when familial clustering and atypical clinical features are present. Despite the patient’s diagnosis at age 48, the detection of the KLF11 c.314G>T (p.Cys105Phe) variant in both her and her children - one of whom has confirmed MODY7 - supports the possibility of a monogenic form of diabetes with incomplete penetrance. Preserved endogenous insulin secretion, absence of autoimmunity, and sustained glycemic control without pharmacologic intervention further reinforce this suspicion. Given the diagnostic complexity, it is essential to propose guidelines for incorporating KLF11 testing into MODY panels, particularly in families showing vertical transmission and mild or atypical diabetes phenotypes. To strengthen genotype-phenotype correlations, we advocate for functional studies, including luciferase reporter assays and beta-cell models, to assess the impact of the p.Cys105Phe variant on insulin gene expression. This approach will help clarify its pathogenicity and refine diagnostic strategies for MODY7.