De novo HNF1A mutation of young maturity-onset diabetes 3 of a young girl-Case report.

Young maturity-onset diabetes of the young type3(MODY3) as a special type of diabetes, the probability of diagnosis is low. This article reports on a case and reviews the relevant knowledge of the disease. We report an 11-year-and-11-month-old girl whose grandmother died from diabetic complications while the rest of the families were non-diabetes. The proband was initially treated with insulin and metformin but the threatment proved inefficient. After an exome-targeted capture sequencing test, she was diagnosed with mature-onset diabetes of young type 3 (MODY3), and sulfonylureas make sense. The key to mody treatment is a correct and timely diagnosis, which contributes to helping patients overcome the problems of MODY3, especially for blood sugar control.

Hepatocellular Adenoma: Report of 2 Cases That Highlight the Relevance of Phenotype-Genotype Correlation in the Pediatric Population.

BACKGROUND: Hepatocellular adenoma (HCA) in the pediatric population is very rare and there are only limited studies, especially with molecular characterization of the tumors. Main HCA subtypes recognized in the current WHO classification include HNF1A-inactivated HCA (H-HCA), inflammatory HCA (IHCA), ß-catenin-activated HCA (b-HCA), and ß-catenin-activated IHCA (b-IHCA) and sonic hedgehog HCA (shHCA) is reported as an emerging subtype. METHODS: Clinical history, pathological information, and molecular studies for a series of 2 cases of pediatric HCA were reviewed. RESULTS: Case 1 was a b-HCA characterized by somatic CTNNB1 S45 mutation in a 11-year-old male with Abernethy malformation. Case 2 was a H-HCA characterized by germline HNF1A variant (c.526+1G>A) in a 15-year-old male associated with maturity-onset diabetes of the young type 3 (MODY3). CONCLUSION: Our findings highlight the rarity of these 2 cases associated with adenomatosis, and the contribution of molecular/genetic analysis for proper sub-typing, prognosis and family surveillance.

A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY.

AIMS/HYPOTHESIS: Systematic studies on the phenotypic consequences of variants causal of HNF1A-MODY are rare. Our aim was to assess the phenotype of carriers of a single HNF1A variant and genetic and clinical factors affecting the clinical spectrum. METHODS: We conducted a family-based multigenerational study by comparing heterozygous carriers of the HNF1A p.(Gly292fs) variant with the non-carrier relatives irrespective of diabetes status. During more than two decades, 145 carriers and 131 non-carriers from 12 families participated in the study, and 208 underwent an OGTT at least once. We assessed the polygenic risk score for type 2 diabetes, age at onset of diabetes and measures of body composition, as well as plasma glucose, serum insulin, proinsulin, C-peptide, glucagon and NEFA response during the OGTT. RESULTS: Half of the carriers remained free of diabetes at 23 years, one-third at 33 years and 13% even at 50 years. The median age at diagnosis was 21 years (IQR 17-35). We could not identify clinical factors affecting the age at conversion; sex, BMI, insulin sensitivity or parental carrier status had no significant effect. However, for 1 SD unit increase of a polygenic risk score for type 2 diabetes, the predicted age at diagnosis decreased by 3.2 years. During the OGTT, the carriers had higher levels of plasma glucose and lower levels of serum insulin and C-peptide than the non-carriers. The carriers were also leaner than the non-carriers (by 5.0 kg, p=0.012, and by 2.1 kg/m2 units of BMI, p=2.2 × 10-4, using the first adult measurements) and, possibly as a result of insulin deficiency, demonstrated higher lipolytic activity (with medians of NEFA at fasting 621 vs 441 µmol/l, p=0.0039; at 120 min during an OGTT 117 vs 64 µmol/l, p=3.1 × 10-5). CONCLUSIONS/INTERPRETATION: The most common causal variant of HNF1A-MODY, p.(Gly292fs), presents not only with hyperglycaemia and insulin deficiency, but also with increased lipolysis and markedly lower adult BMI. Serum insulin was more discriminative than C-peptide between carriers and non-carriers. A considerable proportion of carriers develop diabetes after young adulthood. Even among individuals with a monogenic form of diabetes, polygenic risk of diabetes modifies the age at onset of diabetes.

HNF1A Mutations and Beta Cell Dysfunction in Diabetes.

Understanding the genetic factors of diabetes is essential for addressing the global increase in type 2 diabetes. HNF1A mutations cause a monogenic form of diabetes called maturity-onset diabetes of the young (MODY), and HNF1A single-nucleotide polymorphisms are associated with the development of type 2 diabetes. Numerous studies have been conducted, mainly using genetically modified mice, to explore the molecular basis for the development of diabetes caused by HNF1A mutations, and to reveal the roles of HNF1A in multiple organs, including insulin secretion from pancreatic beta cells, lipid metabolism and protein synthesis in the liver, and urinary glucose reabsorption in the kidneys. Recent studies using human stem cells that mimic MODY have provided new insights into beta cell dysfunction. In this article, we discuss the involvement of HNF1A in beta cell dysfunction by reviewing previous studies using genetically modified mice and recent findings in human stem cell-derived beta cells.

Defective functions of HNF1A variants on BCL2L1 transactivation and beta-cell growth.

Maturity-onset diabetes of the young type 3 (MODY3) is caused by mutations in a gene encoding transcription factor hepatocyte nuclear factor 1-alpha (HNF1A). Although the roles of HNF1A in regulation of hepatic and pancreatic genes to maintain glucose homeostasis were investigated, the functions of HNF1A are not completely elucidated. To better understand the functions of HNF1A, we characterized mutations of HNF1A in Thai MODY3 patients and studied the functions of wild-type HNF1A and variant proteins. We demonstrate for the first time that HNF1A upregulates transactivation of an anti-apoptotic gene BCL2 Like 1 (BCL2L1) and that all the identified HNF1A variants including p.D80V, p.R203C, p.P475L, and p.G554fsX556, reduce this ability. The four HNF1A variants impair HNF1A function in promoting INS-1 cell transition from G1 to S phase of cell cycle, which thereby retard cell growth. This finding indicates the role of HNF1A in beta-cell viability by upregulation of anti-apoptotic gene expression and also reaffirms its role in beta-cell growth through cell cycle control.

Hepatocellular adenoma: Classification, variants and clinical relevance.

Hepatocellular adenomas are benign tumors with two major complications, bleeding and malignant transformation. The overall narrative of hepatocellular adenoma has evolved over time. Solitary or multiple hepatocellular developing in the normal liver of women of child bearing age exposed to oral contraceptives still represents the most frequent clinical context, however, new associations are being recognized. Hepatocellular adenoma is discovered on a background of liver diseases such as non-alcoholic steatohepatitis, vascular diseases, and alcoholic cirrhosis. Hepatocellular adenoma is also reported in men, young or older adults, and even in infants. On the morpho-molecular side, the great leap forward was the discovery that hepatocellular adenoma was not a single entity and that at least 3 different subtypes exist, with specific underlying gene mutations. These mutations affect the HNF1A gene, several genes leading to JAK/STAT3 pathway activation and the CTNNB1 gene. All of them are associated with more or less specific histopathological characteristics and can be recognized using immunohistochemistry either with specific antibodies or with surrogate markers. Liver pathologists and radiologists are the key actors in the identification of the different subtypes of hepatocellular adenoma by the recognition of their specific morphological features. The major impact of the classification of hepatocellular adenoma is to identify subjects who are at higher risk of malignant transformation. With the development of new molecular technologies, there is hope for a better understanding of the natural history of the different subtypes, and, particularly for their mechanisms of malignant transformation.

A 12q24.31 interstitial deletion in an adult male with MODY3: neuropsychiatric and neuropsychological characteristics.

A 39-year-old male patient with a disharmonic intelligence profile and juvenile diabetes mellitus is described. At 14 months of age, minor facial dysmorphisms were noticed. He had delayed motor development, obesity at early age, and a diagnosis of insulin-dependent diabetes at the age of 10 years. He successfully completed secondary education and has been engaged in unskilled work activities, living independently. Upon examination, no psychiatric symptoms were present and his neuropsychological profile showed normal, although disharmonic, intellectual capacities and suboptimal social cognition. Genome wide array analysis identified an interstitial 12q24.31 deletion of 1.67 Mb encompassing hepatocyte nuclear factor-1-alpha gene (HNF1A), supporting a diagnosis of maturity-onset diabetes of the young. Results are discussed in relation to the few identified or published overlapping deletions. This is the first patient with normal intelligence in whom the presence of subtle facial dysmorphisms were decisive for introducing genetic analysis that, in turn, disclosed a rare form of diabetes necessitating modifications in treatment regimen. Clinicians, including those involved in psychiatry, should be aware of the diagnostic and prognostic value of atypical physical features in patients with a long history of complicated glucose regulation.

Chinese carrier of the HNF1A p.Gln444fs variant exhibits enhanced response to sulfonylureas.

Background: We assessed the response to sulfonylureas and the functional characteristics of HNF1A mutations in patients with maturity-onset diabetes of the young type 3 (MODY3). Methods: We recruited a family with suspected MODY in this study, and gene sequencing (whole-exome sequencing) was used to screen germline mutations. Luciferase reporter assays were used to evaluate the activity of the mutated genes. Results: Heterozygous HNF1A variant (NM_000545.8:c.1330_1331del, p.Gln444fs) was identified in the proband and was not found in his father, grandmother, and nonrelated healthy controls. The mutant protein had 552 amino acids, 110 fewer than the wild type protein. Furthermore, the amino acid sequence was completely different between the mutant protein and the wild type protein starting from the 444th amino acid. Luciferase reporter assays revealed that the variant had impaired HNF4A promoter-regulation activity. The patient did not achieve good hypoglycemic effects during long-term treatment with insulin and metformin. The effect of hypoglycemic treatment was highly significant after the addition of sulfonylurea drugs. Conclusions: The HNF1A p.Gln444fs variant associated with MODY3, and most likely a truncated protein, impaired HNF1A transcriptional activity. The variant carrier experienced an enhanced response to sulfonylureas.

Primary hepatocellular neoplasms in a MODY3 family with a novel HNF1A germline mutation.

Maturity onset diabetes of the young type 3 (MODY3) and hepatocellular adenomas (HCAs) are associated with mutations in the HNF1A gene. HNF1A codes for the transcription factor HNF1α, which interacts with DNA as a homodimer or a heterodimer with HNF1ß, to regulate multiple cellular functions including glucidic metabolism, lipidic transport, and detoxication. We report three members of one family with a novel germline in-frame deletion of HNF1A exons 2-3 identified initially using array CGH and direct sequence analysis. All three family members have MODY3 in association with primary liver cell tumours (HCA, liver adenomatosis (LA), and hepatocellular carcinoma (HCC)). Additionally, a high rate of infant mortality was observed in the family. The described family demonstrates a novel HNF1A mutation associated with both benign and malignant primary liver cell tumours and MODY3.

The spectrum of HNF1A gene mutations in Greek patients with MODY3: relative frequency and identification of seven novel germline mutations.

OBJECTIVE: Maturity-Onset Diabetes of the Young (MODY) is the most common type of monogenic diabetes accounting for 1-2% of the population with diabetes. The relative incidence of HNF1A-MODY (MODY3) is high in European countries; however, data are not available for the Greek population. The aims of this study were to determine the relative frequency of MODY3 in Greece, the type of the mutations observed, and their relation to the phenotype of the patients. DESIGN AND METHODS: Three hundred ninety-five patients were referred to our center because of suspected MODY during a period of 15 yr. The use of Denaturing Gradient Gel Electrophoresis of polymerase chain reaction amplified DNA revealed 72 patients carrying Glucokinase gene mutations (MODY2) and 8 patients carrying HNF1A gene mutations (MODY3). After using strict criteria, 54 patients were selected to be further evaluated by direct sequencing or by multiplex ligation probe amplification (MLPA) for the presence of HNF1A gene mutations. RESULTS: In 16 unrelated patients and 13 of their relatives, 15 mutations were identified in the HNF1A gene. Eight of these mutations were previously reported, whereas seven were novel. Clinical features, such as age of diabetes at diagnosis or severity of hyperglycemia, were not related to the mutation type or location. CONCLUSIONS: In our cohort of patients fulfilling strict clinical criteria for MODY, 12% carried an HNF1A gene mutation, suggesting that defects of this gene are responsible for a significant proportion of monogenic diabetes in the Greek population. No clear phenotype-genotype correlations were identified.

Prevalence, clinical features and complications of common forms of Maturity Onset Diabetes of the Young (MODY) seen at a tertiary diabetes centre in south India.

BACKGROUND: Maturity Onset Diabetes of the Young (MODY) is a form of monogenic diabetes caused by mutations in single genes, affecting adolescents or young adults. MODY is frequently misdiagnosed as type 1 diabetes (T1). Though several studies from India have reported on the genetic aspects of MODY, the clinical profile, complications and treatments given have not been reported so far, nor compared with T1D and type 2 diabetes (T2D). AIM: To determine the prevalence, clinical features, and complications of common forms of genetically proven MODY seen at a tertiary diabetes centre in South India and compare them with matched individuals with T1D and T2D. METHODS: Five hundred and thirty individuals identified as 'possible MODY' based on clinical criteria, underwent genetic testing for MODY. Diagnosis of MODY was confirmed based on pathogenic or likely pathogenic variants found using Genome Aggregation Database (gnomAD) and American College of Medical Genetics (ACMG) criteria. The clinical profile of MODY was compared with individuals with type 1 (T1D) and type 2 (T2D) diabetes, matched for duration of diabetes. Retinopathy was diagnosed by retinal photography; nephropathy by urinary albumin excretion > 30 µg/mg of creatinine and neuropathy by vibration perception threshold > 20 v on biothesiometry. RESULTS: Fifty-eight patients were confirmed to have MODY (10.9%). HNF1A-MODY (n = 25) was the most common subtype followed by HNF4A-MODY (n = 11), ABCC8-MODY (n = 11), GCK-MODY (n = 6) and HNF1B-MODY (n = 5). For comparison of clinical profile, only the three 'actionable' subtypes - defined as those who may respond to sulphonylureas, namely, HNF1A, HNF4A and ABCC8-MODY, were included. Age at onset of diabetes was lower among HNF4A-MODY and HNF1A-MODY than ABCC8-MODY, T1D and T2D. Prevalence of retinopathy and nephropathy was higher among the three MODY subtypes taken together (n = 47) as compared to T1D (n = 86) and T2D (n = 86). CONCLUSION: This is one of the first reports of MODY subtypes from India based on ACMG and gnomAD criteria. The high prevalence of retinopathy and nephropathy in MODY points to the need for earlier diagnosis and better control of diabetes in individuals with MODY.

An insulin hypersecretion phenotype precedes pancreatic ß cell failure in MODY3 patient-specific cells.

MODY3 is a monogenic hereditary form of diabetes caused by mutations in the transcription factor HNF1A. The patients progressively develop hyperglycemia due to perturbed insulin secretion, but the pathogenesis is unknown. Using patient-specific hiPSCs, we recapitulate the insulin secretion sensitivity to the membrane depolarizing agent sulfonylurea commonly observed in MODY3 patients. Unexpectedly, MODY3 patient-specific HNF1A+/R272C ß cells hypersecrete insulin both in vitro and in vivo after transplantation into mice. Consistently, we identified a trend of increased birth weight in human HNF1A mutation carriers compared with healthy siblings. Reduced expression of potassium channels, specifically the KATP channel, in MODY3 ß cells, increased calcium signaling, and rescue of the insulin hypersecretion phenotype by pharmacological targeting ATP-sensitive potassium channels or low-voltage-activated calcium channels suggest that more efficient membrane depolarization underlies the hypersecretion of insulin in MODY3 ß cells. Our findings identify a pathogenic mechanism leading to ß cell failure in MODY3.

Treatment strategy for maturity-onset diabetes of the young 3 (MODY3): Experience with two sisters and their mother.

Maturity onset diabetes of the young (MODY) is a relatively young-onset diabetes mellitus with an autosomal dominant inheritance. Among these phenotypes, MODY3, caused by mutations in HNF1A, is one of the most frequent. Although MODY3 is known to respond markedly to sulfonylureas (SU), many cases require insulin therapy. However, there are no clear guidelines for factors to consider when introducing antidiabetic drugs and insulin. This report describes a familial case in which an older sister was diagnosed with diabetes and subsequently with MODY3, followed by the onset of diabetes in the younger sister and mother. The elder sister initially denied insulin treatment and exhibited a suboptimal response to SU but finally agreed to insulin use. The mother initially selected insulin therapy because of the challenges associated with adherence to strict dietary therapy. Conversely, the younger sister responded positively to SU and maintained effective glycemic control. The management of MODY3, even though they have the same single-gene mutation and similar residual insulin secretion at diagnosis, should be flexibly individualized for each family member to ensure long-term adherence and appropriate glycemic control.

Variants of the HNF1α gene: A molecular approach concerning diabetic patients from southern Brazil.

Maturity Onset Diabetes of the Young (MODY) presents monogenic inheritance and mutation factors which have already been identified in six different genes. Given the wide molecular variation present in the hepatocyte nuclear factor-1α gene (HNF1α) MODY3, the aim of this study was to amplify and sequence the coding regions of this gene in seven patients from the Campos Gerais region, Paraná State, Brazil, presenting clinical MODY3 features. Besides the synonymous variations, A15A, L17L, Q141Q, G288G and T515T, two missense mutations, I27L and A98V, were also detected. Clinical and laboratory data obtained from patients were compared with the molecular findings, including the I27L polymorphism that was revealed in some overweight/obese diabetic patients of this study, this corroborating with the literature. We found certain DNA variations that could explain the hyperglycemic phenotype of the patients.

An intron mutation of HNF1A causes abnormal splicing and impairs its activity as a transcription factor.

Mutations in HNF1A are associated with Maturity Onset Diabetes of the Young type 3 (MODY3) and most of them are in the coding region. Herein, we identified an intron mutation at the 6th nucleotide upstream of the end of intron 7 of HNF1A, named IVS7-6G > A, in a patient with early-onset diabetes. The "minigene" assay showed that IVS7-6G > A produced two aberrant mRNA variants translating into two truncated proteins: L502S fs* and G437A fs*, both affecting HNF1A transactivation domain (TAD). To determine functional consequences of IVS7-6G > A mutation, we made plasmids encoding truncated HNF1A containing different portions of HNF1A TAD and found that the TAD of HNF1A is important not only for its regulatory activities, but also for its nuclearization, and the residues 282-501 was more essential than 502-631. Our data suggested IVS7-6G > A impaired HNF1A splicing and may contribute to the pathogenesis of MODY3.

Meta-analysis of HNF1A-MODY3 variants among human population.

Background: Previously, numerous case-control studies have highlighted variants responsible for Maturity onset diabetes of young (MODY). However, these studies have been conducted among diverse populations and hence yielded contradictory results. We, therefore, performed a meta-analysis to precisely find the association of SNPs with the disease for the HNF1A gene. Objective: Meta-analysis of clinically defined studies deciphering mutations in the HNF1A gene responsible for the development of MODY3 was conducted among various populations to determine associations using statistical approaches. Methods: The curation of 505 research articles published between the years 2000-2021 was carried out. Visualization of data-related protocols and statistical-analysis were conducted, which led to the identification of highly prevalent mutations among different populations (majorly Europe). Further comparison between the frequencies of the control (healthy population) and test (diseased population) dataset generated through curation was performed. Results: We identified nine MODY3 mutations (rs587776825, rs1169288, rs1800574, rs2464196, rs137853244, rs137853238, rs587780357, rs137853240 and rs137853243) at the genome-wide significance level ( p < 5.0 × 10-8). The present study confirmed that the data does not follow a normal distribution. Further, the data was confirmed to be a more homogenous type with frequencies having a significant association with the disease. Conclusion: This meta-analysis found significant associations of mutations in HNF1A with MODY3, consistent with previous studies. Our findings should help elucidate the mutations in a compiled form responsible for causing MODY3. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-022-00975-8.

HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus.

Diabetes, a disease characterized by hyperglycemia, has a serious impact on the lives and families of patients as well as on society. Diabetes is a group of highly heterogeneous metabolic diseases that can be classified as type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes mellitus (GDM), or other according to the etiology. The clinical manifestations are more or less similar among the different types of diabetes, and each type is highly heterogeneous due to different pathogenic factors. Therefore, distinguishing between various types of diabetes and defining their subtypes are major challenges hindering the precise treatment of the disease. T2D is the main type of diabetes in humans as well as the most heterogeneous. Fortunately, some studies have shown that variants of certain genes involved in monogenic diabetes also increase the risk of T2D. We hope this finding will enable breakthroughs regarding the pathogenesis of T2D and facilitate personalized treatment of the disease by exploring the function of the signal genes involved. Hepatocyte nuclear factor 1 homeobox A (HNF1α) is widely expressed in pancreatic ß cells, the liver, the intestines, and other organs. HNF1α is highly polymorphic, but lacks a mutation hot spot. Mutations can be found at any site of the gene. Some single nucleotide polymorphisms (SNPs) cause maturity-onset diabetes of the young type 3 (MODY3) while some others do not cause MODY3 but increase the susceptibility to T2D or GDM. The phenotypes of MODY3 caused by different SNPs also differ. MODY3 is among the most common types of MODY, which is a form of monogenic diabetes mellitus caused by a single gene mutation. Both T2D and GDM are multifactorial diseases caused by both genetic and environmental factors. Different types of diabetes mellitus have different clinical phenotypes and treatments. This review focuses on HNF1α gene polymorphisms, HNF1A-MODY3, HNF1A-associated T2D and GDM, and the related pathogenesis and treatment methods. We hope this review will provide a valuable reference for the precise and individualized treatment of diabetes caused by abnormal HNF1α by summarizing the clinical heterogeneity of blood glucose abnormalities caused by HNF1α mutation.

Cytokine Profile in Patients With Maturity-onset Diabetes of the Young (MODY).

BACKGROUND/AIM: High-sensitivity C-reactive protein (hs-CRP) is used in the differential diagnosis of maturity-onset diabetes of the young (MODY)-3, but other inflammatory markers have not been investigated in MODY patients. We aimed to compare the serum levels of anti-inflammatory and proinflammatory cytokines between MODY patients and healthy subjects and show the inflammatory features in MODY subtypes. PATIENTS AND METHODS: Thirty patients with clinically suspected MODY and 34 healthy controls were included in this study. Next-generation sequencing (NGS) was used for the molecular diagnosis of MODY subtypes. Serum levels of cytokines were measured using a multiplexed cytokine assay and hs-CRP concentration was determined by the immunoturbidimetric assay. RESULTS: The hs-CRP levels were higher in both NGS-confirmed (MODY, n=17) (p=0.009) and NGS-unconfirmed (non-MODY, n=13) patients (p<0.001) than those in controls. However, IL-1ß (p=0.001), IL-6 (p=0.018), IL-31 (p=0.003), TNF-α (p<0.001), and sCD40L (p=0.007) levels of MODY patients and IL-1ß (p=0.002), IL-31 (p<0.001), IL-22 (p=0.018), and sCD40L (p=0.039) levels of non-MODY patients were lower than those of controls. While hs-CRP levels were lower in MODY3 patients than non-MODY3 patients (p=0.009), IL-17A (p=0.006) and IL-23 (p=0.016) levels for the first time in this study were found to be higher in patients with MODY3 than in patients with other MODY subtypes (p<0.05). CONCLUSION: MODY patients had lower serum levels of the proinflammatory cytokines IL-1ß, IL-6, TNF-α, IL-31, and sCD40L compared to healthy controls. High IL-17A and IL-23 levels along with low hs-CRP levels may be potential markers to distinguish MODY3 from other MODY subtypes.