Triple genetic variation in the HNF-4alpha gene is associated with early-onset type 2 diabetes mellitus in a philippino family

Maturity-onset diabetes of the young-type 1 (MODY1) is a form of monogenic type 2 diabetes mellitus (T2DM) with long-term complications due to mutations in the HNF-4alpha gene. The HNF-4alpha gene is involved in hepatic differentiation and expression of genes regulating glucose transport, glycolysis, and lipid metabolism. The abnormal glucose-stimulated insulin secretion in MODY1 subjects may be due to reduced glucose transport and glycolysis. To date, 14 mutations in the HNF-4alpha gene have been identified as a cause of either MODY1 or late-onset type 2 diabetes. So far, no screening has been performed in subjects from the Philippines. We recruited a Philippino family with autosomal dominant early-onset type 2 diabetes and screened the proband for mutations in the genes for HNF-1alpha, GCK, HNF-4alpha, IPF-1, HNF-6, and NGN3. We identified a new missense mutation in exon 5 (V199I) of the HNF-4alpha gene and 2 new single-nucleotide substitutions in intron 4, IVS4-nt4 (G --> A) and IVS4-nt20 (C --> T), all cosegregating with diabetes in the 3 affected available siblings. These variations were not present in 100 normal healthy subjects. Bioinformatic analysis suggests that these variations in the whole, and overall the IVS4-nt4 variation located at splicing site, may affect the splicing potential of intron 4. We have biochemically and clinically characterized the Philippine-1 family. We suggest that the V199I missense mutation located in the ligand binding/dimerization domain of HNF-4alpha contributes to type 2 diabetes in the Philippine-1 family. The intron variations may contribute susceptibility to diabetes.     

A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young

Summary Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin dependent diabetes mellitus (NIDDM) characterised by an early age of onset (< 25 years) and an autosomal dominant mode of inheritance. MODY is genetically heterogeneous with three different genes identified to date; hepatocyte nuclear factor 4 alpha (HNF-4α) [MODY1], glucokinase [MODY2] and hepatocyte nuclear factor 1 alpha (HNF-1α) [MODY3]. A nonsense mutation in the HNF-4α gene has recently been shown to cause MODY in a single large North American pedigree (RW). We screened a large UK Caucasian MODY family which showed weak evidence of linkage to the MODY1 locus on chromosome 20q (lod score for ADA 0.68 at θ = 0) for mutations in the coding region of the HNF-4α gene by direct sequencing. A missense mutation resulting in the substitution of glutamine for glutamic acid was identified in exon 7 (E276Q). The mutation was present in all of the diabetic members of the pedigree plus two unaffected subjects and was not detected in 75 normal control subjects or 95 UK Caucasian subjects with late-onset NIDDM. This is the first missense mutation to be described in the HNF-4α gene. [Diabetologia (1997) 40: 859–862] Received: 7 March 1997 and in revised form: 16 April 1997     

Genetic epidemiology of MODY in the Czech republic: new mutations in the MODY genes <Emphasis Type="Italic">HNF-4α</Emphasis>, <Emphasis Type="Italic">GCK</Emphasis> and <Emphasis Type="Italic">HNF-1α</Emphasis>

AIMS/HYPOTHESIS: The aim of this study was to examine the prevalence and nature of mutations in HNF4alpha/MODY1, GCK/MODY2 and HNF-1alpha/MODY3 genes in Czech subjects with clinical diagnosis of MODY. METHODS: We studied 61 unrelated index probands of Czech origin (28 males, 33 females) with a clinical diagnosis of MODY and 202 family members. The mean age of probands was 22.7+/-12.0 years (range, 6-62) and the mean age at the first recognition of hyperglycaemia was 14.7+/-6.0 years (range, 1-25). The promotor and coding regions inclusive intron exon boundaries of the HNF-4alpha, GCK and HNF-1alpha genes were examined by PCR-dHPLC (HNF-1alpha and GCK) and direct sequencing. RESULTS: We identified 20 different mutations in the HNF-4alpha, GCK and HNF-1alpha in 29 families (48% of all families studied), giving a relative prevalence of 5% of MODY1, 31% of MODY2 and 11.5% of MODY3 among the Czech kindred with MODY. Three of 3, 10 of 11 and 1 of 6 of the mutations identified in HNF-4alpha, GCK and HNF-1alpha respectively, were new. CONCLUSION/INTERPRETATION: Of the families 48% carried mutations in the MODY1-3 genes and of the identified mutations 70% were new. In 52% of Czech families with clinical characteristics of MODY, no mutations were found in the analysed genes. This finding shows that the majority of MODY mutations in a central European population are local and that other MODY genes could be responsible for autosomal dominant transmission of diabetes mellitus.     

High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes

Abstract Aims/hypothesis. To investigate the contribution of mutations in maturity-onset diabetes of the young (MODY) and mitochondrial genes to early-onset diabetes with a strong family history of diabetes in a cohort with a high prevalence of Type I (insulin-dependent) diabetes mellitus. Methods. Screening for sequence variants in the hepatocyte nuclear factor (HNF)–4 α (MODY1), glucokinase (MODY2), HNF-1 α (MODY3) genes and mitochondrial DNA was carried out in 115 Finnish and Swedish patients with early-onset ( ≤ 40 years) diabetes using the single strand conformation polymorphism (SSCP) technique and direct sequencing. Allele frequencies were compared with 118 patients with onset of diabetes Type II (non-insulin-dependent) diabetes mellitus after the age of 40 and 92 non–diabetic control subjects without a family history of diabetes. Results. In total 52 sequence variants were found in the HNF-1α, HNF-4α and glucokinase genes, 12 of which were considered as MODY mutations. Three families had the A3243G mutation in the mitochondrial tRNA ^Leu gene, which resulted in an overall prevalence of these mutations of 13 %. Conclusion/interpretation. Among 115 Scandinavian families, mutations in the HNF-1α gene represented the most common cause of familial early-onset ( ≤ 40 years) diabetes: MODY3 (5.2 %) more than MODY2 (3.5 %) more than MIDD (2.6 %) more than MODY1 (1.7 %). [Diabetologia (1999) 42: 1131–1137] Received: 3 March 1999 and in revised form: 14 May 1999     

Mutations of maturity-onset diabetes of the young (MODY) genes in Thais with early-onset type 2 diabetes mellitus

Objective  Six known genes responsible for maturity-onset diabetes of the young (MODY) were analysed to evaluate the prevalence of their mutations in Thai patients with MODY and early-onset type 2 diabetes.
Patients and methods  Fifty-one unrelated probands with early-onset type 2 diabetes, 21 of them fitted into classic MODY criteria, were analysed for nucleotide variations in promoters, exons, and exon–intron boundaries of six known MODY genes, including HNF-4α , GCK , HNF-1α , IPF-1 , HNF-1β , and NeuroD1/β2 , by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method followed by direct DNA sequencing. Missense mutations or mutations located in regulatory region, which were absent in 130 chromosomes of non-diabetic controls, were classified as potentially pathogenic mutations.
Results  We found that mutations of the six known MODY genes account for a small proportion of classic MODY (19%) and early-onset type 2 diabetes (10%) in Thais. Five of these mutations are novel including GCK R327H, HNF-1α P475L, HNF-1α G554fsX556, NeuroD1 –1972 G > A and NeuroD1 A322N. Mutations of IPF-1 and HNF-1β were not identified in the studied probands.
Conclusions  Mutations of the six known MODY genes may not be a major cause of MODY and early-onset type 2 diabetes in Thais. Therefore, unidentified genes await discovery in a majority of Thai patients with MODY and early-onset type 2 diabetes.     

High frequency of mutations in the HNF-1alpha gene in non-obese patients with diabetes of youth in Japanese and identification of a case of digenic inheritance

AIMS/HYPOTHESIS: There is an emerging epidemic of Type II (non-insulin-dependent) diabetes mellitus of youth in Japan and in many other developed countries. The aim of this study was to determine the prevalence of mutations in the hepatocyte nuclear factor (HNF)-1alpha gene (TCF1) in a large group of Japanese patients with early-onset non-Type I (insulin-dependent) diabetes mellitus. Since approximately 20% of Caucasian patients with HNF-1alpha mutations have been shown to be obese or overweight, we also examined the association of genetic variations in TCF1 with body weight in Japanese subjects. METHODS: We examined 203 patients with non-Type 1 diabetes who had been diagnosed before they reached 15 years of age. Ten exons and flanking introns of TCF1 of these patients were directly sequenced for mutations. RESULTS: We found 14 different mutations in 18 patients (8.9%), including one that was found to be de novo. The patients with the mutations had lower BMI (20.1+/-3.0 kg/m(2)) at diagnosis than the patients without them (24.5+/-6.0 kg/m(2)) (p=0.0024). All of the patients with the mutations, except for one, Y120, had normal body weight (BMI<25 kg/m(2)); the frequency of HNF-1alpha mutations in the non-obese patients of this study was 17% (17/101). Patient Y120, who had atypical symptoms of mild obesity and insulin resistance at diagnosis, was found to have inherited an additional mutation in an obesity-related gene. CONCLUSION/INTERPRETATION: A considerable number of non-obese Japanese patients with non-Type 1 diabetes of youth have HNF-1alpha-deficient diabetes. Lack of obesity could well be a characteristic feature of this form of diabetes.     

Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1alpha gene mutations: evidence for pharmacogenetics in diabetes.

INTRODUCTION: Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominantly inherited, early-onset, non-insulin-dependent diabetes. Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene are the commonest cause of MODY. Individual patients with HNF-1alpha mutations have been reported as being unusually sensitive to the hypoglycaemic effects of sulphonylurea therapy. We report three patients, attending a single clinic, with HNF-1alpha mutations that show marked hypersensitivity to sulphonylureas. CASE REPORTS: In cases 1 and 2 there were marked changes in HbA1c on cessation (4.4% and 5.8%, respectively) and reintroduction (5.0% and 2.6%) of sulphonylureas. Case 3 had severe hypoglycaemic symptoms on the introduction of sulphonylureas despite poor glycaemic control and was shown with a test dose of 2.5 mg glibenclamide to have symptomatic hypoglycaemia (blood glucose 2 mmol/l) after 4 h despite eating. CONCLUSIONS: HNF-1alpha MODY diabetic subjects are more sensitive to sulphonylureas than Type 2 diabetic subjects and this is seen in different families, with different mutations and may continue up to 13 years from diagnosis. This is an example of pharmacogenetics, with the underlying aetiological genetic defect altering the pharmacological response to treatment. The present cases suggest that in HNF-1alpha MODY patients: (i) sulphonylureas can dramatically improve glycaemic control and should be considered as initial treatment for patients with poor glycaemic control on an appropriate diet; (ii) hypoglycaemia may complicate the introduction of sulphonylureas and therefore very low doses of short acting sulphonylureas should be used initially; and (iii) cessation of sulphonylureas should be undertaken cautiously as there may be marked deterioration in glycaemic control.     

Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families

The aims of this study were to estimate the prevalence of major maturity-onset diabetes of the young (MODY) subtypes in Spanish MODY families and to analyze genotype-phenotype correlations. Twenty-two unrelated pediatric MODY patients and 97 relatives were screened for mutations in the coding region of the glucokinase (GCK), hepatic nuclear factor- HNF-1alpha and HNF4alpha genes using PCR-single strand conformation polymorphism and/or direct sequencing. In families carrying GCK mutations, the influence of genetic defects on fetal growth was investigated by comparing the birth weights of 32 offspring discordant for the mutations. Mutations in MODY genes were identified in 64% of the families. GCK/MODY2 mutations were the most frequently found, in 41%: seven novel (R369P, S411F, M298K, C252Y, Y108C, A188E, and S383L) and 2 already described mutations. Four pedigrees (18%) harbored mutations in the HNF-1alpha/MODY3 gene, including a previously unreported change (R271G). One family (4%) carried a novel mutation in the HNF-4alpha gene (IVS5-2delA), representing the first report of a MODY1 pedigree in the Spanish population. The age at diagnosis was prepubertal in MODY2 index patients and pubertal in MODY3 patients. Overt diabetes was rare in MODY2 and was invariably present in MODY3 index patients. Chronic complications of diabetes were absent in the MODY2 population and were present in more than 40% of all relatives of MODY3. Birth weight was lower in the presence of a GCK fetal mutation when the mutation was of paternal origin. The MODY1 patient was diagnosed at 15 yr of age. She developed intermittent microalbuminuria despite good metabolic control, and severe late-onset complications were common within her family. Mutations in the GCK/MODY2 gene are the most common cause of MODY in our population as recruited from pediatric and adolescent index patients. The inheritance of GCK defects by the fetus results in a reduction of birth weight. Clinical expression of MODY3 and MODY1 mutations, the second and third groups of defects found, was more severe, including the frequent development of chronic complications.     

A novel mutation in the hepatocyte nuclear factor-1alpha/MODY3 gene in Chinese subjects with early-onset Type 2 diabetes mellitus in Taiwan.

AIMS: The goal of this study was to determine the frequency of mutation in hepatic nuclear factor (HNF)-1alpha, a gene recently implicated as causing maturity-onset diabetes of the young (MODY) and to analyse the respective clinical presentations in an ethnically Chinese population. METHODS: Fifteen unrelated subjects (nine females and six males) aged less than 35 years who had early-onset diabetes were analysed to test the possibility that mutation of the HNF-1alpha gene was responsible for this disorder. Genomic DNA extraction, polymerase chain reaction and DNA sequence analysis were performed accordingly. RESULTS: One patient with MODY had a novel missense mutation in exon 3 of the HNF-1alpha gene (Y218C) in a region of the protein that corresponds to a predicted DNA binding domain. CONCLUSIONS: A Y218C mutation in HNF-1alpha gene was identified in one family in Taiwan.