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P Froguel

Publications and source records attributed to P Froguel.

At least 91 records · Page 5Linked to original sources
PubMed1999

Type 2 diabetes mellitus: association study of five candidate genes in an Indian population of Guadeloupe, genetic contribution of FABP2 polymorphism.

We studied by PCR-RFLP 6 polymorphisms in these 5 candidate genes: Ala54Thr in the fatty acid binding protein 2 gene (FABP2), A to G substitution in the uncoupling protein type 1 gene (UCP1), Asp905Tyr in the protein phosphatase type 1 gene (PP1G), Trp64Arg in the human beta 3 adrenergic receptor gene (beta 3AR) and 2 RFLP sites of the vitamin D receptor (VDR) gene (VDRTaq1 and VDRApa1). This study was conducted among 89 cases and 100 controls matched according to age, gender and absence of first degree family link (11 triplets with 2 controls for 1 case and 78 pairs with 1 control for 1 case). Cases and controls were taken among a sample of 429 individuals selected for the study of the prevalence of diabetes in this ethnic group from Guadeloupe. By conditional logistic regression analysis, there was a significant relation (p = 0.02) between the Ala54Thr FABP2 polymorphism and Type 2 DM. Multivariate analysis discriminate the FABP2 polymorphism (p = 0.10), a triglyceridemia over 2 g/l (p < 10(-3)) and high blood pressure (p = 10(-2)) as variables associated with Type 2 DM in this population. These findings suggest that FABP2 does not represent a major gene for Type 2 DM in this migrant Indian population living in Guadeloupe, but seems to be related to the metabolic insulin resistance syndrome.

Adult↗
PubMed1999

Absence of replication in the French population of the association between beta 2/NEUROD-A45T polymorphism and type 1 diabetes.

BETA 2/NEUROD1 is a key regulator of pancreatic islet morphogenesis and insulin gene transcription. The BETA 2/NEUROD1 gene-locus lies on human chromosome 2q32, in a region previously linked to Type 1 diabetes (IDDM7). Recently, a significant association has been reported between NEUROD1-A45T polymorphism and Type 1 diabetes in the Japanese population. In an attempt to replicate this observation, we performed a case/control study in the French population. We failed to find any association between the A45T polymorphism and the disease-trait. The study therefore suggests that NEUROD1 is unlikely to play a major role in susceptibility to Type 1 diabetes in the French population.

Adult↗
PubMed1998

Nuclear factors and type 2 diabetes.

Recent studies have shown that mutations in four transcription factors, hepatocyte nuclear factor-4 alpha (HNF-4 alpha), hepatocyte nuclear factor-1 alpha (HNF-1 alpha), hepatocyte nuclear factor-1 beta (HNF-1 beta), and insulin promoter factor-1 (IPF-1), are responsible for maturity onset diabetes of the young (MODY) which is characterised by an early age of onset and autosomal dominant inheritance. MODY is not an uncommon disorder and in fact could account for about 2 to 5% of all cases of type 2 diabetes. Moreover, mutations in HNF-1 beta, which functions as a homodimer or a heterodimer with HNF-1 alpha, have been identified in a few families with MODY and severe kidney disease. Mutations in the coding regions or in the promotors of these nuclear factors are responsible for severe insulin secretory defects and for major hyperglycaemia associated with microvascular complications. The role of transcription factors in the development of the more common late-onset type 2 diabetes is still under investigation. Some mutations in HNF-1 alpha were identified in subjects with atypical forms of insulin-dependent diabetes, and a mutation in HNF-4 alpha and several mutations in IPF-1 were found in type 2 diabetic families with typical late-onset NIDDM. Altogether, these data suggest that non-MODY monofactorial forms of late-onset NIDDM, due to islet transcription factor defects, exist.

Adult↗
PubMed1998

Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice.

Mutations in the gene for the transcription factor hepatocyte nuclear factor (HNF) 1alpha cause maturity-onset diabetes of the young (MODY) 3, a form of diabetes that results from defects in insulin secretion. Since the nature of these defects has not been defined, we compared insulin secretory function in heterozygous [HNF-1alpha (+/-)] or homozygous [HNF-1alpha (-/-)] mice with null mutations in the HNF-1alpha gene with their wild-type littermates [HNF-1alpha (+/+)]. Blood glucose concentrations were similar in HNF-1alpha (+/+) and (+/-) mice (7.8+/-0.2 and 7.9+/-0.3 mM), but were significantly higher in the HNF-1alpha (-/-) mice (13.1+/-0.7 mM, P < 0.001). Insulin secretory responses to glucose and arginine in the perfused pancreas and perifused islets from HNF-1alpha (-/-) mice were < 15% of the values in the other two groups and were associated with similar reductions in intracellular Ca2+ responses. These defects were not due to a decrease in glucokinase or insulin gene transcription. beta cell mass adjusted for body weight was not reduced in the (-/-) animals, although pancreatic insulin content adjusted for pancreas weight was slightly lower (0.06+/-0.01 vs. 0.10+/-0.01 microg/mg, P < 0.01) than in the (+/+) animals. In summary, a null mutation in the HNF-1alpha gene in homozygous mice leads to diabetes due to alterations in the pathways that regulate beta cell responses to secretagogues including glucose and arginine. These results provide further evidence in support of a key role for HNF-1alpha in the maintenance of normal beta cell function.

Animals↗
PubMed1998

A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction.

The adipocyte-specific hormone leptin, the product of the obese (ob) gene, regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family. In rodents, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadisms. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.

Adult↗
PubMed1998

A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4alpha) in families with maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose-stimulated insulin secretion. During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age. Thus, we screened these families for mutations in the HNF-4alpha gene. We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family. This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family.

Age of Onset↗
PubMed1998

Leptin receptor gene in a large cohort of massively obese subjects: no indication of the fa/fa rat mutation. Detection of an intronic variant with no association with obesity.

The massive obesity caused in rodents by the disruption of the leptin-receptor signal through genetic defects at the level of either leptin (OB) or leptin receptor (OB-R) has raised the question of the relevance of these genes to morbid obesity in humans. In this study, we screened a large population of massively obese subjects for the presence of a leptin receptor mutation homologous to that of fa/fa rats, a single base substitution changing glutamine 269, a highly conserved glutamine found at position 270 in the human sequence. After polymerase chain reaction (PCR) amplification of a DNA region encompassing the end of exon 5, intron 5, and the beginning of exon 6, we performed restriction fragment length polymorphism analysis. Within the limitations of this approach where only mutations introducing restriction sites (5 of 8 possibilities) could be assessed, no evidence of mutation at the codon gln 270 was found in 343 massively obese subjects. However, a new OB-R gene variant in intron 5 was revealed by MaeII digestion of the PCR products. MaeII/hOB-R genotyping revealed no difference in the distribution of the genotypes between obese subjects and a group of 79 unrelated nonobese control subjects. In addition, no significant association between various obesity-related metabolic phenotypes and the presence of MaeII/hOB-R alleles was found. Thus, our results did not support a significant role for the MaeII/hOB-R gene variant in the development of the obese phenotype in the population we studied.

Adult↗
PubMed1998

Mutation screening in 18 Caucasian families suggest the existence of other MODY genes.

Maturity-onset diabetes of the young (MODY) is a heterogeneous subtype of non-insulin-dependent diabetes mellitus characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date five MODY genes have been identified: hepatocyte nuclear factor-4 alpha (HNF-4alpha/MODY1/TCF14) on chromosome 20q, glucokinase (GCK/MODY2) on chromosome 7p, hepatocyte nuclear factor-1 alpha (HNF-1alpha/MODY3/TCF1) on chromosome 12q, insulin promoter factor-1 (IPF1/MODY4) on chromosome 13q and hepatocyte nuclear factor-1 beta (HNF-1beta/MODY5/TCF2) on chromosome 17cen-q. We have screened the HNF-4alpha, HNF-1alpha and HNF-1beta genes in members of 18 MODY kindreds who tested negative for glucokinase mutations. Five missense (G31D, R159W, A161T, R200W, R271W), one substitution at the splice donor site of intron 5 (IVS5nt + 2T-->A) and one deletion mutation (P379fsdelT) were found in the HNF-1alpha gene, but no MODY-associated mutations were found in the HNF-4alpha and HNF-1beta genes. Of 67 French MODY families that we have now studied, 42 (63%) have mutations in the glucokinase gene, 14 (21%) have mutations in the HNF-1alpha gene, and 11 (16%) have no mutations in the HNF-4alpha, IPF1 and HNF-1beta genes. Eleven families do not have mutations in the five known MODY genes suggesting that there is at least one additional locus that can cause MODY.

Adult↗
PubMed1998

Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians.

The K+ inwardly rectifier channel (KIR) is one of the two sub-units of the pancreatic islet ATP-sensitive potassium channel complex (I(KATP)), which has a key role in glucose-stimulated insulin secretion and thus is a potential candidate for a genetic defect in Type II (non-insulin-dependent) diabetes mellitus. We did a molecular screening of the KIR6.2 gene by single strand conformational polymorphism (SSCP) and direct sequencing in 72 French Caucasian Type II diabetic families. We identified three nucleotide substitutions resulting in three amino acid changes (E23K, L270V and 1337V), that have also been identified in other Caucasian Type II diabetic subjects. These variants were genotyped in French cohorts of 191 unrelated Type II diabetic probands and 119 normoglycaemic control subjects and association studies were done. The genotype frequencies of the L270V and 1337V variants were not very different between Type II diabetic subjects and control groups. In contrast, analysis of the E23K variant showed that the KK homozygocity was more frequent in Type II diabetic than in control subjects (27 vs 14%, p = 0.015). Analyses in a recessive model (KK vs EK/EE) tended to show a stronger association of the K allele with diabetes (p = 0.0097, corrected p-value for multiple testing < 0.02). The data for the E23K variant obtained here and those obtained from three other Caucasian groups studied so far were combined and investigated by meta-analysis. Overall, the E23K variant was found to be significantly associated with Type II diabetes (0.001 < or = p < or = .00106, corrected p-values for multiple testing p < or = 0.01). This study shows that KIR6.2 polymorphisms are frequently associated with Type II diabetes in French Caucasians. Furthermore, a meta-analysis combining different Caucasian groups suggests an significant role of KIR6.2 in the polygenic context of Type II diabetes.

Aged↗
PubMed1998

A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10.

Obesity, a common multifactorial disorder, is a major risk factor for type 2 diabetes, hypertension and coronary heart disease (CHD). According to the definition of the World Health Organization (WHO), approximately 6-10% of the population in Westernized countries are considered obese. Epidemiological studies have shown that 30-70% of the variation in body weight may be attributable to genetic factors. To date, two genome-wide scans using different obesity-related quantitative traits have provided candidate regions for obesity. We have undertaken a genome-wide scan in affected sibpairs to identify chromosomal regions linked to obesity in a collection of French families. Model-free multipoint linkage analyses revealed evidence for linkage to a region on chromosome 10p (MLS=4.85). Two further loci on chromosomes 5cen-q and 2p showed suggestive evidence for linkage of serum leptin levels in a genome-wide context. The peak on chromosome 2 coincided with the region containing the gene (POMC) encoding pro-opiomelanocortin, a locus previously linked to leptin levels and fat mass in a Mexican-American population and shown to be mutated in obese humans. Our results suggest that there is a major gene on chromosome 10p implicated in the development of human obesity, and the existence of two further loci influencing leptin levels.

Alleles↗
PubMed1998

A polymorphism in the 5' untranslated region of the human ob gene is associated with low leptin levels.

OBJECTIVE: To search the human ob gene for mutations and evaluate their role in massive obesity. DESIGN: Direct mutation screening of the gene and case-control association study. Multivariate analyses for evaluation of differences in clinical parameters. SUBJECTS: Primary mutation screening: 24 morbidly obese subjects (body mass index (BMI) > 40 kg/m2). Association study: 395 unrelated morbidly obese subjects (BMI > 40 kg/m2), 121 lean, non-diabetic control individuals, 72 women of a random sample with an average BMI 32.5 kg/m2. RESULTS: We report the finding of a DNA variant in exon 1 of the human ob gene (A --> G substitution, base + 19). This variant showed a prevalence of 62% in our study population. Association analyses under different genetic models (dominant, co-dominant, recessive) showed no significant evidence for an association of this variant with BMI. However, obese individuals homozygous for the G-allele showed significantly lower leptin concentrations compared to obese patients either heterozygous or homozygous for the A-allele after correction for BMI. CONCLUSION: Recent linkage studies have shown evidence for linkage of the hsob locus with obesity. Our study provides further evidence that a defect in the ob gene in linkage disequilibrium with the G-allele of exon 1 might be involved in obesity by affecting leptin concentrations.

Adult↗
PubMed1998

Genetic, metabolic and clinical characteristics of maturity onset diabetes of the young.

Maturity onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of non-insulin-dependent diabetes mellitus (NIDDM) characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date, three MODY genes have been identified on chromosomes 20q (MODY1/hepatic nuclear factor (HNF)-4alpha), 7p (MODY2/glucokinase) and 12q (MODY3/HNF-1alpha). Mutations in MODY2/glucokinase result in mild chronic hyperglycaemia as a result of reduced pancreatic beta-cell responsiveness to glucose, and decreased net accumulation of hepatic glycogen and increased hepatic gluconeogenesis after meals. In contrast, MODY1 and MODY3 are characterised by severe insulin secretory defects, and by major hyperglycaemia associated with microvascular complications. The role of the three known MODY genes in susceptibility to the more common late-onset NIDDM remain uncertain. Genetic studies seem to exclude a role as major susceptibility genes, but leave unresolved whether they may have a minor role in a polygenic context or an important role in particular populations.

Adolescent↗