SEARCH · Search PubMed

Results for “MODY”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources

PubMed2000

Proposed mechanism for a novel insertion/deletion frameshift mutation (I414G415ATCG-->CCA) in the hepatocyte nuclear factor 1 alpha (HNF-1 alpha) gene which causes maturity-onset diabetes of the young (MODY).

Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin dependent diabetes (NIDDM) characterized by an early age of diagnosis (usually < 25 years) and an autosomal dominant mode of inheritance. Mutations in the hepatocyte nuclear factor 1 alpha (HNF-1alpha) [MODY3] gene represent the most common cause of MODY in the UK and a common cause of MODY in many other populations. Sixty-three different mutations have been described in a total of 112 families worldwide. This report describes two families, not known to be related, who carry a novel insertion/deletion mutation (I414G415ATCG-->CCA) and a 6bp intronic deletion of the HNF-1alpha gene in cis. We propose that the insertion/deletion mutation has arisen by formation of a hairpin loop due to the presence of a quasi-palindromic sequence, followed by insertion of CC and deletion of TCG resulting in the increased stability of the hairpin loop.

Adult↗

PubMed2005

Identification of novel GCK and HNF1A/TCF1 mutations and polymorphisms in German families with maturity-onset diabetes of the young (MODY).

Maturity-onset diabetes of the young is a genetically heterogeneous autosomal dominant form of diabetes mellitus, characterized by an early age at onset and a primary defect in beta-cell function. Forty families with a clinical presentation suggestive of MODY were screened for the most common MODY subtypes caused by mutations in the genes encoding glucokinase (GCK, MODY2) and hepatocyte nuclear 1-alpha (HNF1A/TCF1, MODY3). Overall, 14 mutations were found (35%) giving a relative frequency of 22.5% and 12.5% for MODY2 and MODY3, respectively. Five of the nine GCK mutations identified were novel and included two deletions, two nonsense, and one splice site mutation. The GCK splice donor mutation was shown to result in an aberrant transcript owing to the recruitment of a cryptic splice site. The translated protein is predicted to contain an in frame insertion of nine amino acids. Among the five HNF1A mutations identified, three were novel comprising one missense mutation, one deletion, and one insertion. In addition, several novel polymorphisms within GCK were identified and their allele frequencies estimated. Knowledge of the genetic cause of MODY has significant impact on therapeutic decision making and may help to identify family members at risk for diabetes.

Adolescent↗

PubMed2000

MODY associated with two novel hepatocyte nuclear factor-1alpha loss-of-function mutations (P112L and Q466X).

Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of diabetes characterized by early onset of pancreatic dysfunction. MODY type 3 is caused by mutations in the hepatocyte nuclear factor (HNF)-1alpha. During a screening of Norwegian patients with suspected MODY we identified two novel HNF-1alpha mutations, P112L and Q466X. The molecular mechanisms underlying the disease were studied by analyzing the DNA binding properties, transcriptional activation, and subcellular localization of HNF-1alpha P112L and Q466X compared to wild type HNF-1alpha. P112L had reduced ability to bind an HNF1 consensus sequence and to activate transcription. Q466X did not differ from wild type HNF-1alpha in DNA binding activity. Transactivation, however, was markedly reduced. When both mutants were coexpressed with wild type HNF-1alpha in HeLa cells, transcriptional activity appeared unaffected, suggesting that a dominant-negative mechanism was not present. Immunolocalization experiments showed that P112L HNF-1alpha was correctly targeted to nuclei in HeLa cells. In contrast, some Q466X HNF-1alpha protein was retained in the cytoplasm, which indicated that the mechanism for nuclear localization was disturbed. Thus, the HNF-1alpha mutations P112L and Q466X both seem to impair pancreatic beta-cell function by loss-of-function mechanisms; P112L by reduced DNA binding and reduced ability to transactivate, and Q466X by reduced transactivation and incomplete nuclear targeting.

DNA↗

PubMed2002

Mutations in the hepatocyte nuclear factor-1alpha gene in Chinese MODY families: prevalence and functional analysis.

AIMS/HYPOTHESIS: Maturity-onset diabetes of the young is an autosomal dominant form of diabetes characterised by an early age of onset (usually <25 years). We investigated the prevalence and trans-activating activity of hepatocyte nuclear factor (HNF) -1 alpha mutations in southern Chinese families with MODY. METHODS: We screened for mutations in the HNF-1 alpha gene in 50 unrelated southern Chinese families, which fulfilled the minimum criteria for MODY. Functional properties of the mutant proteins were investigated using site-directed mutagenesis and luciferase reporter assay. RESULTS: Five of the 50 (10%) families were found to have mutations in the coding region, including a new nonsense mutation Q176X and four reported mutations (frameshift mutation P379fsdelCT, nonsense mutation R171X, missense mutations G20R and P112L). These mutations had decreased trans-activating activity on the human insulin gene promoter. We also detected a new intronic sequence variation IVS7nt-6 G-->A, which co-segregated with diabetes. The intronic variation creates a potential splice acceptor site and might alter the splicing of the HNF-1 alpha mRNA. CONCLUSION/INTERPRETATION: Mutations in the HNF-1 alpha gene seem to be an important cause of MODY in southern Chinese. The mutations could affect normal islet function by altering the expression of target genes.

Amino Acid Substitution↗

PubMed2006

Common variants in MODY genes increase the risk of gestational diabetes mellitus.

AIMS/HYPOTHESIS: Impaired beta cell function is the hallmark of gestational diabetes mellitus (GDM) and MODY. In addition, women with MODY gene mutations often present with GDM, but it is not known whether common variants in MODY genes contribute to GDM. SUBJECTS AND METHODS: We genotyped five common variants in the glucokinase (GCK, commonly known as MODY2), hepatocyte nuclear factor 1-alpha (HNF1A, commonly known as MODY3) and 4-alpha (HNF4A commonly known as MODY1) genes in 1,880 Scandinavian women (648 women with GDM and 1,232 pregnant non-diabetic control women). RESULTS: The A allele of the GCK -30G-->A polymorphism was more common in GDM women than in control subjects (odds ratio [OR] 1.28 [95% CI 1.06-1.53], p=0.008, corrected p value, p=0.035). Under a recessive model [AA vs GA+GG], the OR increased further to 2.12 (95% CI 1.21-3.72, p=0.009). The frequency of the L allele of the HNF1A I27L polymorphism was slightly higher in GDM than in controls (1.16 [95% CI 1.001-1.34], p=0.048, corrected p value, p=0.17). However, the OR increased under a dominant model (LL+IL vs II; 1.31 [95% CI 1.08-1.60], p=0.007). The rs2144908, rs2425637 and rs1885088 variants, which are located downstream of the primary beta cell promoter (P2) of HNF4A, were not associated with GDM. CONCLUSIONS/INTERPRETATION: The -30G-->A polymorphism of the beta-cell-specific promoter of GCK and the I27L polymorphism of HNF1A seem to increase the risk of GDM in Scandinavian women.

Adult↗

PubMed1988

One Japanese MODY family with severe and progressive microangiopathies.

Recently we investigated maturity-onset diabetes of the young (MODY) with severe and progressive microangiopathies in one Japanese family. The proband was a female who was diagnosed as having diabetes when she was 11 years old, and was controlled without insulin for 9 years. She is now 30 years old and has been suffering from proliferative retinopathy since the age of 20. Her maternal grandfather, mother, uncle, and younger sister are also diabetic with severe microangiopathies. MODY is a concept which was first put forward by Tattersall and Fajans in 1975. It was defined as a form of diabetes diagnosed before the age of 25 years, controlled without insulin for more than 2 years and demonstrating dominant heredity over more than three generations. Most Western papers have reported few microangiopathies in the MODY patient, but our findings run counter to this description.

Adult↗

PubMed2001

Predictive genetic testing in maturity-onset diabetes of the young (MODY).

INTRODUCTION: Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominant inheritance of young-onset non-insulin-dependent diabetes. It accounts for approximately 1% of Type 2 diabetes (approximately 20 000 people in the UK). Diagnostic and predictive genetic tests are now possible for 80% of MODY families. Diagnostic tests can be helpful as the diagnosis can be confirmed and the subtype defined which has implications for treatment and prognosis. However predictive genetic testing, particularly in children, raises many scientific, ethical and practical questions. METHODS: This is a case report of a family with diabetes resulting from an hepatic nuclear factor (HNF)1alpha mutation, who request a predictive test in their 5-year-old daughter. The scientific issues arising from molecular genetic testing in MODY are discussed, along with the process of genetic counselling. The views of the family and the clinical genetics team involved are presented. RESULTS: The implications of positive and negative predictive test results and the possibility of postponing the test were among many issues discussed during genetic counselling. The family remained convinced the test was appropriate for their daughter and the clinical genetics team fully supported this decision. The family, motivated by their family history of diabetes and personal experiences of the disease, wished to reduce uncertainty about their daughter's future irrespective of the result. CONCLUSIONS: This case emphasizes that decisions on predictive testing are very personal and require appropriate counselling.

Adolescent↗

PubMedDate not supplied

[MODY, a model of genotype/phenotype interactions in type 2 diabetes].

Maturity onset diabetes of the young (MODY) is a subtype of familial diabetes mellitus characterised by early onset, autosomal dominant inheritance and primary defects of insulin secretion. Mutations in six known genes (the enzyme glucokinase and five transcription factors expressed in pancreatic beta-cells) cause most of the MODY cases. This genetic heterogeneity is associated with metabolic and clinical heterogeneity making MODY an interesting model of genotype/phenotype interaction in diabetes.

DNA-Binding Proteins↗

PubMed1983

[Clinical variability of autosomal-dominant juvenile diabetes (MODY)].

Occurrence prior to the age of 25 years, dominant inheritance, metabolic control without insulin for more than two years and mild course without late complications are considered characteristic of maturity-onset diabetes of young people (MODY). Diabetes or glucose tolerance disturbance was observed in 30 members of a family in five successive generations. The course of the disease within the family was variable: even after disease for several decades no diabetes-specific late complications were seen in 20 diabetics, six, in contrast, had serious complications such as proliferative retinopathy, nephropathy and coma. The different clinical course is expression of the considerable variability of this genetically uniform metabolic disorder. Our observations demonstrate that vascular complications in MODY are less frequent than in type II diabetes, however are not excluded. Thus, also MODY diabetics require life-long careful metabolic surveillance.

Adult↗

PubMed2003

Rescue of MODY-1 by agonist ligands of hepatocyte nuclear factor-4alpha.

Missense mutations of the ligand binding domain of hepatocyte nuclear factor (HNF)-4alpha result in maturity onset diabetes of the young (MODY)-1. We show here that MODY-1 as well as Gln-185 missense mutants of the ligand binding domain of HNF-4alpha fail to transactivate transcription of HNF-4alpha-responsive genes. Defective transactivation by these mutants is accounted for by their reduced binding affinities for fatty acyl agonist ligands of HNF-4alpha. These mutants may be rescued by exogenous fatty acid agonist ligands of HNF-4alpha, yielding transcriptional activities in the wild type range. The effect of added ligands is synergistic with that of transcriptional coactivators of HNF-4alpha. These findings may indicate the means for treating selected MODY-1 subjects with HNF-4alpha agonist nutrients and drugs.

Acyl Coenzyme A↗

PubMed1989

Proliferative diabetic retinopathy in a patient with maturity-onset diabetes of the young (MODY).

Maturity-onset diabetes of the young (MODY) has been described as being characteristically free from severe complications. This has led to speculation that the type of diabetes may be important in the pathogenesis of complications in diabetes. We report a case of classical MODY in which severe proliferative diabetic retinopathy developed. The retinopathy was detected shortly after the diagnosis of diabetes was made when the patient was 32 years old, and did not progress subsequently. No further complications developed during the subsequent 29 years in which normal postprandial plasma glucose levels were maintained with chlorpropamide therapy (mean 4.7, range 4.1-6.0 mmol I-1). This case demonstrates that severe retinopathy can occur in MODY and we suggest that in this patient there may have been a period of hyperglycaemia prior to diagnosis which was sufficient to lead to the microvascular complication.

Adolescent↗

PubMed2005

Diagnostic screening of NEUROD1 (MODY6) in subjects with MODY or gestational diabetes mellitus.

AIMS: Diagnostic screening of NEUROD1 in patients with maturity-onset diabetes of the young (MODY) without mutations in the known MODY-genes (MODYX) and in subjects diagnosed with gestational diabetes mellitus. METHODS: Direct sequencing of NEUROD1 was performed in (i) 73 probands with clinical MODY without mutations in hepatocyte nuclear factor (HNF)-4alpha (MODY1), glucokinase (MODY2) and hepatocyte nuclear factor (HNF)-1alpha (MODY3), and (ii) 51 subjects diagnosed with gestational diabetes. Control material consisted of 105 anonymous blood donors. RESULTS: Mean age at diagnosis of diabetes was 22 and 30 years in the MODYX patients and gestational diabetes mellitus subjects, respectively. Mean fasting blood glucose (9.6 +/- 4.3 vs. 5.7 +/- 1.0 mml/l) as well as glycosylated haemoglobin (8.2 +/- 2.4 vs. 6.0 +/- 0.6%) were higher in the MODYX patients than subjects with gestational diabetes. NEUROD1 mutations were not detected in our two study groups. Three previously reported polymorphisms were found: Ala45Thr, Pro197His and IVS1 -32 nt C>T. The amino acid substitution serine to cysteine in codon 29 (designated Ser29Cys) was detected in one out of 105 control subjects. As the control material consisted of anonymous blood donors, we were prevented from investigation of possible co-segregation between the sequence variant Ser29Cys and diabetes mellitus. CONCLUSIONS: As we found no NEUROD1 mutations, diagnostic screening for this gene is not warranted in Norwegian MODYX patients. Our study also suggests that NEUROD1 is not a candidate gene in gestational diabetes mellitus (GDM). The sequence variant Ser29Cys was identified in one anonymous DNA sample, but we were prevented from studying possible co-segregation with diabetes mellitus.

Adult↗

PubMed2006

[Young adult onset diabetes mellitus. Clinical differences between MODY-3 and type 2 diabetes mellitus].

BACKGROUND AND OBJECTIVE: The aim of our study was to evaluate the clinical and metabolic characteristics of type 2 diabetes diagnosed in young adults (T2DYA) and in subjects with mutations in HNF-1* gene. PATIENTS AND METHOD: We included 8 subjects diagnosed of MODY-3 (3 women) at ages 25-45. They were matched (1/2) by gender and age of diagnosis with 16 (6 women) T2DYA. Clinical and metabolic characteristics, as well as C-reactive protein levels, were evaluated. RESULTS: There were not differences in terms of age, disease duration and family history of type 2 diabetes. MODY-3 subjects had a lower body mass index -24 (3) vs. 31 (4) kg/m2; P = .000- and in a lower proportion they had hypertension and required insulin treatment. High density lipoprotein-cholesterol value was higher -50 (4) vs. 43 (2) mg/dl; P = .000) and HbA1c -7.1% (1,0%) vs. 8.2% (1,2%); P = .036-, triglycerides -147 (17) vs. 184 (20) mg/dl; P = .000- and C-reactive protein -0.6 (0,2) vs. 1.7 (0,6) mg/l; P = .000- levels were lower in subjects with MODY-3. CONCLUSIONS: The presence of clinical and metabolic features related to metabolic syndrome could be of help in order to differentiate between T2DYA and diabetes due to mutations in HNF-1*.

Adult↗

PubMed2026

Progressive HNF1A-MODY pathophysiology revealed by a translational mouse model.

HNF1A-MODY, the most common monogenic diabetes, exhibits progressive β cell dysfunction, but existing mouse models fail to recapitulate human disease progression, limiting understanding of pathogenic mechanisms. We developed mice with heterozygous deletion of the Hnf1a transactivation domain (Hnf1a+/Δe4-10) to model human HNF1A haploinsufficiency, conducted cross-sectional metabolic characterization, and validated our findings in HNF1A-deficient human islets. Unlike previous models, Hnf1a+/Δe4-10 mice successfully recapitulated temporal HNF1A-MODY progression. Male mice developed sequential pathophysiology: early insulin resistance in young adults (7 weeks), followed by testosterone deficiency and fasting hyperglycemia in adult mice (10 weeks). Glucose intolerance emerged in middle-aged mice (30 weeks), progressing to multi-organ dysfunction in aged mice (44-70 weeks), characterized by elevated hepatic gluconeogenesis, impaired renal glucose handling, and hepatic steatosis/fibrosis. This dual pathophysiology involving β cell dysfunction and peripheral insulin resistance was associated with dysregulated hormone secretion from both α and β cells in aged mice (40-70 weeks). Human islet studies with HNF1A knockdown confirmed translational relevance, demonstrating reduced SGLT2 protein expression and inappropriate glucagon and insulin secretion. This work established a physiologically relevant HNF1A-MODY model, identified early insulin resistance as a key mechanism triggering hormonal dysfunction, and revealed HNF1A's role in multi-organ pathophysiology beyond traditional β cell dysfunction.

Animals↗

PubMed1999

A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse.

The mouse autosomal dominant mutation Mody develops hyperglycemia with notable pancreatic beta-cell dysfunction. This study demonstrates that one of the alleles of the gene for insulin 2 in Mody mice encodes a protein product that substitutes tyrosine for cysteine at the seventh amino acid of the A chain in its mature form. This mutation disrupts a disulfide bond between the A and B chains and can induce a drastic conformational change of this molecule. Although there was no gross defect in the transcription from the wild-type insulin 2 allele or two alleles of insulin 1, levels of proinsulin and insulin were profoundly diminished in the beta cells of Mody mice, suggesting that the number of wild-type (pro)insulin molecules was also decreased. Electron microscopy revealed a dramatic reduction of secretory granules and a remarkably enlarged lumen of the endoplasmic reticulum. Little proinsulin was processed to insulin, but high molecular weight forms of proinsulin existed with concomitant overexpression of BiP, a molecular chaperone in the endoplasmic reticulum. Furthermore, mutant proinsulin expressed in Chinese hamster ovary cells was inefficiently secreted, and its intracellular fraction formed complexes with BiP and was eventually degraded. These findings indicate that mutant proinsulin was trapped and accumulated in the endoplasmic reticulum, which could induce beta-cell dysfunction and account for the dominant phenotype of this mutation.

Alleles↗

PubMed2004

Assessment of rice fields by GIS/GPS-supported classification of MODIS data.

The new Moderate-Resolution Imaging Spectroradiometer (MODIS) satellite image offers a large choice of opportunities for operational applications. The 1-km Advanced Very High Resolution Radiometer (AVHRR) image is not suitable for retrieval of field level parameter and Landsat data are not frequent enough for monitoring changes in crop parameters during the critical crop growth periods. A methodology to map areas of paddy fields using MODIS, geographic information system (GIS) and global position system (GPS) is introduced in this paper. Training samples are selected and located with the help of GPS to provide maximal accuracy. A concept of assessing areas of potential cultivation of rice is suggested by means of GIS integration. By integration of MODIS with GIS and GPS technologies the actual areas of rice fields in 2002 have been mapped. The classification accuracy was 95.7% percent compared with the statistical data of the Agricultural Bureau of Zhejiang Province.

Agriculture↗

PubMed1995

No evidence for mutations in a putative beta-cell ATP-sensitive K+ channel subunit in MODY, NIDDM, or GDM.

The beta-cell ATP-sensitive K+ (K-ATP) channel has a major role in glucose-induced insulin secretion. Screening the entire coding sequence of the gene for a putative beta-cell K-ATP channel subunit, K-ATP2, with single-strand conformation polymorphism did not show any mutations associated with diabetes in white Caucasian diabetic patients, including five pedigrees with maturity onset diabetes of the young (MODY), 25 patients with noninsulin-dependent diabetes mellitus (NIDDM) selected for marked beta-cell deficiency, 25 selected for mild diabetes presenting before age 50 years with fasting plasma glucose levels < 10 mmol/l, 25 unselected NIDDM patients, and 25 subjects with gestational diabetes mellitus (GDM) and subsequent raised fasting plasma glucose. In five large MODY pedigrees, linkage analysis with simple tandem-repeat polymorphisms (STRPs) near the K-ATP2 gene excluded linkage. In a population association study, no linkage disequilibrium for the STRP was found between 237 unselected white Caucasian NIDDM patients and 104 geographically matched and age-matched white Caucasian nondiabetic subjects. In addition, two silent polymorphisms were found with similar frequency in nondiabetic and diabetic subjects. Mutations in the gene for K-ATP2 are unlikely to be a major cause of MODY, NIDDM, or GDM.

Adenosine Triphosphate↗

PubMed1999

Characterization of glucokinase mutations associated with maturity-onset diabetes of the young type 2 (MODY-2): different glucokinase defects lead to a common phenotype.

Glucokinase (GK) is expressed in the pancreatic beta-cells and liver, and plays a key role in the regulation of glucose homeostasis. The enzymatic activity and thermal stability of wild-type (WT) GK and several mutant forms associated with maturity-onset diabetes of the young type 2 (MODY-2) were determined by a steady-state kinetic analysis of the purified expressed proteins. The eight MODY-2 mutations studied were Ala53Ser, Val367Met, Gly80Ala, Thr168Pro, Arg36Trp, Thr209Met, Cys213Arg, and Val226Met. These missense mutations were shown to have variable effects on GK kinetic activity. The Gly80Ala and Thr168Pro mutations resulted in a large decrease in Vmax and a complete loss of the cooperative behavior associated with glucose binding. In addition, the Gly80Ala mutation resulted in a sixfold increase in the half-saturating substrate concentration (S0.5) for ATP, and Thr168Pro resulted in eight- and sixfold increases in the S0.5 values for ATP and glucose, respectively. The Thr209Met and Val226Met mutations exhibited three- and fivefold increases, respectively, in the S0.5 for ATP, whereas the Cys213Arg mutation resulted in a fivefold increase in the S0.5 for glucose. These mutations also led to a small yet significant reduction in Vmax. Of all the mutations studied, only the Cys213Arg mutation had reduced enzymatic activity and decreased thermal stability. Two mutants, Ala53Ser and Val367Met, showed kinetic and thermal stability properties similar to those of WT. These mutants had increased sensitivities to the known negative effectors of GK activity, palmitoyl-CoA, and GK regulatory protein. Taken together, these results illustrate that the MODY-2 phenotype may be linked not only to kinetic alterations but also to the regulation of GK activity.

Adaptor Proteins, Signal Transducing↗