Glucokinase gene mutations are not a common cause of permanent neonatal diabetes in France.
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Adolescent↗
Biomedical subjects
P Froguel
Publications and source records attributed to P Froguel.
The genetic abnormality in the beta cell determines the response to an oral glucose load.
AIMS/HYPOTHESIS: We assessed how the role of genes genetic causation in causing maturity-onset diabetes of the young (MODY) alters the response to an oral glucose tolerance test (OGTT). METHODS: We studied OGTT in 362 MODY subjects, from seven European centres; 245 had glucokinase gene mutations and 117 had Hepatocyte Nuclear Factor -1 alpha ( HNF-1alpha) gene mutations. RESULTS: BMI and age were similar in the genetically defined groups. Fasting plasma glucose (FPG) was less than 5.5 mmol/l in 2 % glucokinase subjects and 46 % HNF-1 alpha subjects ( p < 0.0001). Glucokinase subjects had a higher FPG than HNF-1 alpha subjects ([means +/- SD] 6.8 +/- 0.8 vs 6.0 +/- 1.9 mmol/l, p < 0.0001), a lower 2-h value (8.9 +/- 2.3 vs 11.2 +/- 5.2 mmol/l, p < 0.0001) and a lower OGTT increment (2-h - fasting) (2.1 +/- 2.3 vs 5.2 +/- 3.9 mmol/l, p < 0.0001). The relative proportions classified as diabetic depended on whether fasting (38 % vs 22 %, glucokinase vs HNF-1 alpha) or 2-h values (19 % vs 44 %) were used. Fasting and 2-h glucose values were not correlated in the glucokinase subjects ( r = -0.047, p = 0.65) but were strongly correlated in HNF-1 alpha subjects ( r = 0.8, p < 0.001). Insulin concentrations were higher in the glucokinase subjects throughout the OGTT. CONCLUSION/INTERPRETATION: The genetic cause of the beta-cell defect results in clear differences in both the fasting glucose and the response to an oral glucose load and this can help diagnostic genetic testing in MODY. OGTT results reflect not only the degree of hyperglycaemia but also the underlying cause.
Adult↗
No association between the G482S polymorphism of the proliferator-activated receptor-gamma coactivator-1 (PGC-1) gene and Type II diabetes in French Caucasians.
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Amino Acid Substitution↗
Mutation screening of the urocortin gene: identification of new single nucleotide polymorphisms and association studies with obesity in French Caucasians.
A linkage between obesity-related phenotypes and the 2p21-23 locus has been reported previously. The urocortin (UCN) gene resides at this interval, and its protein decreases appetite behavior, suggesting that UCN may be a candidate gene for susceptibility to obesity. We localized the UCN gene by radiation hybrid mapping, and the surrounding markers were genotyped in a collection of French families. Evidence for linkage was shown between the marker D2S165 and leptin levels (LOD score, 1.34; P = 0.006) and between D2S2247 and the z-score of body mass index (LOD score, 1.829; P = 0.0019). The gene was screened for SNPs in 96 obese patients. Four new variants were established. Two single nucleotide polymorphisms were located in the promoter (-535 A-->G, -286 G-->A), one in intron 1 (+31 C-->G), and one in the 3'-untranslated region (+34 C-->T). Association studies in cohorts of 722 unrelated obese and 381 control subjects and transmission disequilibrium tests, performed for the two frequent promoter polymorphisms, in 120 families (894 individuals) showed that no association was present between these variants and obesity, obesity-related phenotypes, and diabetes. Thus, our analyses of the genetic variations of the UCN gene suggest that, at least in French Caucasians, they do not represent a major cause of obesity.
Adult↗
Rapid SNP allele frequency determination in genomic DNA pools by pyrosequencing.
Individual genotyping of single nucleotide polymorphisms (SNPs) remains expensive, especially for linkage disequilibrium mapping strategies involving high-throughput SNP genotyping. On one hand, current methods may suit scientific and laboratory needs in regard to accuracy, reproducibility/robustness, and large-scale application. On the other hand, a cheaper and less time-consuming alternative to individual genotyping is the use of SNP allelefrequencies determined in DNA pools. We have developed an accurate and reproducible protocol for allele frequency determination using Pyrosequencing technology in large genomic DNA pools (374 individuals). The measured correlation (R2) in large DNA pools was 0.980. In the context of disease-associated SNPs studies, we compared the allele frequencies between the disease (e.g., type 2 diabetes and obesity) and control groups detected by either individual genotyping or Pyrosequencing of DNA pools. In large pools, the variation between the two methods was 1.5 +/- 0.9%. It may be concluded that the allele frequency determination protocol could reliably detect over 4% differences between populations. The method is economical in regard to amounts of DNA, PCR, and primer extension reagents required. Furthermore, it allows the rapid determination of allelefrequency differences in case/control groups for association studies and susceptibility gene discovery in complex diseases.
Diabetes Mellitus↗
Prevalence of the missense mutation Gly574Ser in the hepatocyte nuclear factor-1alpha in Africans with diabetes.
BACKGROUND: Clinical presentation and natural history of diabetes are somewhat different in Black Africans compared to Caucasians. This peculiar disease course could be at least partly related to a specific genetic profile that has not been studied in this population. METHODS: Medical backgrounds, anthropometric and biologic parameters were obtained from 69 diabetic subjects in Dakar, Senegal, in 1998. Blood anti GAD and Islet Cell Antibodies were studied, using RIA and immunofluorescence assay. The HNF-1alpha gene was sequenced searching the Gly574Ser mutation, previously described in MODY 3. RESULTS: Among these 69 diabetic patients, 11 (16%) were found to have the G574S mutation affecting the HNF-1alpha. These 11 patients carrying the mutation were compared respectively with the 58 non carriers. Mean age (57.5 yr. +/- 11 vs 51.1 yr. +/- 15) and duration of diabetes (11.9 vs 6.7 yr), were similar in the two groups. BMI was not different in patients with the mutation (26.3 vs 23.3, p=0.06). Metabolic control (Glycosylated hemoglobin) was poor in the two groups (9.5% vs 9.2%). Chronic complications were equally found in the patients, but no mutation carrier had macroangiopathy. None of the anti GAD positive or ICA positive patients had the mutation. CONCLUSIONS: The HNF-1alpha Gly574Ser mutation was found in 16% of cases in a 69 diabetic patients group in Senegal. Diabetes was as severe as in non carriers of mutation. This mutation has been implicated in atypical diabetes of Afro-American children. The study confirms its prevalence in Africans with diabetes.
Adult↗
Allelic variation in exon 18 of the sulfonylurea receptor 1 (SUR1) gene, insulin secretion and insulin sensitivity in nondiabetic relatives of type 2 diabetic subjects.
BACKGROUND: We have previously observed associations of the T-allele of the exon 18 variant (ACC --> ACT; Thr759Thr) of the sulfonylurea receptor 1 (SUR1) gene with type 2 diabetes mellitus (T2DM). Here we assess beta-cell function and insulin sensitivity in carriers of different genotypes at this locus. METHODS: Pre-hepatic insulin secretion rates (ISR) derived by deconvolution of circulating C-peptide levels, and glucose clearance were assessed during graded infusions of intravenous glucose in CC-homozygous (n=6) and CT-heterozygous (n=6) nondiabetic relatives of CT-heterozygous type 2 diabetic subjects. RESULTS: Average ISR over the duration of the study, adjusted for sex, age, BMI and prevailing glucose levels, were lower in CT-heterozygous subjects as compared with CC-homozygous subjects (3.91 +/- 0.40 vs. 4.84 +/- 0.28 pmol/kg x min(-1); p=0.048). The correlation curves relating ISR to glucose levels were significantly different in the two groups (analyses of covariance p=0.029). Glucose clearance was similar in both groups. CONCLUSIONS: Insulin secretion rates, but not insulin sensitivity, assessed during graded infusion of glucose were mildly decreased in nondiabetic relatives of type 2 diabetic subjects, who carry the at risk T-allele of exon 18 variant of the SUR1 gene. These results suggest that the at-risk allele might have a small effect on pancreatic B-cell function and contribute to the development of T2DM in these families.
ATP-Binding Cassette Transporters↗
A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27.
Prevalence of coronary heart disease (CHD), of type 2 diabetes (T2DM) and of the metabolic syndrome are in Mauritius amongst the highest in the world. As T2DM and CHD are closely associated and have both a polygenic basis, we conducted a 10 cM genome scan with 403 microsatellite markers in 99 independent families of North-Eastern Indian origin including 535 individuals. Families were ascertained through a proband with CHD before 52 years of age and additional sibs with myocardial infarction (MI) or T2DM. Model-free two-point and multipoint linkage analysis were performed using the Mapmarker-Sibs (MLS) and maximum-likelihood-binomial (MLB) programs for autosomal markers and the Aspex program for chromosome X markers. In a second step, additional markers were studied to increase the genetic map density in three regions on chromosomes 3, 8 and 16 where initial indication for linkage was found. Our data show suggestive linkage with CHD on chromosome 16p13-pter with the MLS statistics at 8.69 cM (LOD = 3.06, P = 0.00017) which partially overlaps with a high pressure (HBP) peak. At the same locus, a nominal indication for linkage with T2DM was found in 35 large T2DM Pondicherian families also having Indian origin. With respect to region 8q23, we found suggestive linkage with T2DM (LOD = 2.55, P = 0.00058) as well as with HBP. On 3q27, we replicated previous indication for linkage found in Caucasians (for the metabolic syndrome and for diabetes) according to the categorized trait for CHD and MI with the MLB statistics (LOD = 2.13, P = 0.0009). The genome scan also revealed nominal evidence of linkage with CHD on 10q23 (LOD = 2.06, P = 0.00188). Interestingly, we detected in the same region overlapping linkages with three QTLs: age of onset of CHD (LOD = 2.03), HDL cholesterol (LOD = 1.48) and LDL/HDL ratio (LOD = 1.34). Ordered-subset analysis based on family body mass index ranking replicated finding on 2q37 for T2DM (at Calpain 10 locus). These results show the first evidence for susceptibility loci that predispose to CHD, T2DM and HBP in the context of the metabolic syndrome.
Chromosome Mapping↗
Cloning and characterization of the human and rat islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) genes.
Islet-specific glucose-6-phosphatase (G6Pase) catalytic subunit-related protein (IGRP) is a homolog of the catalytic subunit of G6Pase, the enzyme that catalyzes the terminal step of the gluconeogenic pathway. Its catalytic activity, however, has not been defined. Since IGRP gene expression is restricted to islets, this suggests a possible role in the regulation of islet metabolism and, hence, insulin secretion induced by metabolites. We report here a comparative analysis of the human, mouse, and rat IGRP genes. These studies aimed to identify conserved sequences that may be critical for IGRP function and that specify its restricted tissue distribution. The single copy human IGRP gene has five exons of similar length and coding sequence to the mouse IGRP gene and is located on human chromosome 2q28-32 adjacent to the myosin heavy chain 1B gene. In contrast, the rat IGRP gene does not appear to encode a protein as a result of a series of deletions and insertions in the coding sequence. Moreover, rat IGRP mRNA, unlike mouse and human IGRP mRNA, is not expressed in islets or islet-derived cell lines, an observation that was traced by fusion gene analysis to a mutation of the TATA box motif in the mouse/human IGRP promoters to TGTA in the rat sequence. The results provide a framework for the further analysis of the molecular basis for the tissue-restricted expression of the IGRP gene and the identification of key amino acid sequences that determine its biological activity.
Amino Acid Sequence↗
Genetic and environmental nature of the insulin resistance syndrome in Indo-Mauritian subjects with premature coronary heart disease: contribution of beta3-adrenoreceptor gene polymorphism and beta blockers on triglyceride and HDL concentrations.
AIMS/HYPOTHESIS: Insulin resistance syndrome is an important risk factor for developing premature coronary heart disease. It is a complex syndrome which could arise from the interaction of several genes modulated by environmental factors. The Trp64Arg polymorphism in the beta3-adrenoreceptor gene has been found to be associated with insulin resistance, obesity or with earlier onset of Type II (non-insulin-dependent) diabetes mellitus in different populations. We aimed to study whether features of the insulin resistance syndrome are associated with this polymorphism in Indo-Mauritian patients with premature coronary heart disease. METHODS: We carried out a case control study using PCR-RFLP techniques, of consecutive Indo-Mauritian patients (n = 338) with premature coronary heart disease (onset below age of 60 years) and unrelated control subjects (n = 148) of the same ethnicity. RESULTS: In Indo-Mauritian patients with premature coronary heart disease who were not treated by beta blockers, triglyceride concentrations were lower (median: 1.44 vs 1.93 mmol/l, p < 0.008) and HDL cholesterol concentrations higher (mean: 0.98 vs 0.85 mmol/l, p < 0.015) in those carrying the wild type of the beta3-adrenoreceptor gene than in those carrying the Trp64Arg variant. The latter genotype specific effect on HDL was inverse in patients treated with beta blockers. CONCLUSION/INTERPRETATION: The beta3-adrenoreceptor gene variant seems to modulate the effects of beta blockers on triglyceride and HDL cholesterol concentrations in this group of Indo-Mauritian population. Dyslipidaemia, a key component of the metabolic syndrome has a heterogeneous nature in Indo-Mauritian subjects. This potent risk factor for early-onset coronary heart disease is influenced by the interaction between genetic and environmental effects.
Adrenergic beta-Antagonists↗
Routine mutation screening of HNF-1alpha and GCK genes in MODY diagnosis: how effective are the techniques of DHPLC and direct sequencing used in combination?
AIMS/HYPOTHESIS: Mutations in the hepatocyte nuclear factor (HNF)-1alpha and glucokinase (GCK) genes are the major causes of monogenic forms of Type II (non-insulin-dependent) diabetes mellitus (Maturity-Onset Diabetes of the Young subtypes, MODY). We evaluated the effectiveness of fluorescent single-strand conformation polymorphism (F-SSCP), denaturing high-performance liquid chromatography (DHPLC) and sequencing based mutation detection in the molecular diagnosis of MODY. Our goal is to identify a rapid, efficient and cost effective mutation detection method for the molecular diagnosis of MODY and other human genetic disorders. METHODS: We evaluated the accuracy of DHPLC in screening for MODY 2 and 3 mutations. In addition, we compared the sensitivity, specificity, cost, handling time and analysis time of fluorescent single-strand conformation polymorphism, denaturing high-performance liquid chromatography and direct sequencing screening methods. RESULTS: Denaturing high-performance liquid chromatography is a recently developed method for mutation detection. It is cost effective, powerful and reliable and quite suitable for 22 out of the 24 fragments required for MODY 2 and 3 testing. However, exons 1 and 7 of the HNF-1alpha gene are very polymorphic and so direct sequencing is faster as well as more efficient and reliable. CONCLUSION/INTERPRETATION: Our results suggest that combining denaturing high-performance liquid chromatography and direct sequencing is a good approach for the routine detection of HNF-1alpha and GCK mutations in MODY families. Denaturing high-performance liquid chromatography appears to be a powerful tool in genetic testing and the method could be applied to the molecular diagnosis of other human genetic diseases.
Base Sequence↗
No evidence for diabetes-associated mutations of PEK/EIF2AK3 gene in French patients with early-onset type II diabetes.
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Age of Onset↗
Polymorphism analysis of JRK/JH8, the human homologue of mouse jerky, and description of a rare mutation in a case of CAE evolving to JME.
Disruption of the function of the mouse jerky gene by transgene insertion causes generalized recurrent seizures reminiscent of human idiopathic generalized epilepsy (IGE). A human homologue, JRK/JH8, has been cloned, which maps to 8q24, a chromosomal region associated with several forms of IGE. JRK/JH8 is, therefore, a candidate locus for at least some forms of IGE. We report corrected cDNA sequences and extended open reading frames for the mouse jerky and human JRK/JH8 genes, which add 48 amino acids to the N-terminus of the Jerky protein and which extends the region of homology with the N-terminal DNA-binding domain of the centromere-binding protein, CENP-B. Systematic sequencing of the coding region of the extended JRK/JH8 gene identified single nucleotide polymorphisms that define three haplotypes, which were used for association studies in patients with idiopathic generalized epilepsy. We report one subject with childhood absence epilepsy (CAE) that evolved to juvenile myoclonic epilepsy (JME) that has a unique de novo mutation that results in a non-conservative amino acid change at a potential protein glycosylation site. Familial analysis supports a causal role for this mutation in the disease.
Alleles↗
The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.
Adiponectin is an adipocyte-derived hormone. Recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where the gene encoding adiponectin is located. Here we show that decreased expression of adiponectin correlates with insulin resistance in mouse models of altered insulin sensitivity. Adiponectin decreases insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. This effect results from increased expression of molecules involved in both fatty-acid combustion and energy dissipation in muscle. Moreover, insulin resistance in lipoatrophic mice was completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either adiponectin or leptin alone. We conclude that decreased adiponectin is implicated in the development of insulin resistance in mouse models of both obesity and lipoatrophy. These data also indicate that the replenishment of adiponectin might provide a novel treatment modality for insulin resistance and type 2 diabetes.
Adiponectin↗
Genetics of human obesity.
Obesity is a multifactorial condition. Environmental risk factors related to a sedentary life-style and unlimited access to food apply constant pressure in subjects with a genetic predisposition to gain weight. The fact that genetic defects can result in human obesity has been unequivocally established over the past 3 years with the identification of the genetic defects responsible for different monogenic forms of human obesity: the leptin, leptin receptor, pro-opiomelanocortin, pro-hormone convertase-1 and melanocortin-4 receptor genes. The common forms of obesity are, however, polygenic. The examination of specific genes for involvement in the susceptibility to common obesity has not yet yielded convincing results. Approaches involving the candidate genes and the positional cloning of major obesity-linked regions (state-of-the-art future prospects) will be discussed.
Aspartic Acid Endopeptidases↗
Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children.
OBJECTIVE: To search for mutations in melanocortin pathway elements, that is, the melanocortin-4 receptor (MC4R ), agouti-related protein (AGRP ), and (alpha-melanocyte-stimulating hormone (alpha MSH ) genes in children with severe obesity. STUDY DESIGN: Direct sequencing of the MC4R encoding sequence and single-strand polymorphism conformation analysis of AGRP and alpha MSH genes were performed in 63 severely obese children. Polymerase chain reaction (PCR) assays of restriction fragment length polymorphism were used to assess the frequency of each newly discovered mutation in 283 non-obese control subjects. RESULTS: Four dominantly inherited, heterozygous, missense MC4R mutations (Val50Met, Ser58Cys, Ile102Ser, and Ile170Val) were identified in 4 unrelated children and none of the control subjects. Expression of the obese phenotype was variable in mutation-positive family members. Clinical and laboratory features were similar in the obese children with and without an MC4R mutation. Two polymorphisms were detected in the AGRP -encoding sequence (a silent mutation in exon 1 and Ala67Thr in exon 2), with similar frequencies in the obese and control groups. No mutations were found in the alpha MSH gene. CONCLUSIONS: MC4R mutations may be a non-negligible cause of severe obesity in children with variable expression and penetrance. Mutations in AGRP and alpha MSH genes were not among the causes of obesity in our population.
Adolescent↗
Molecular and cytogenetic characterisation of a small interstitial de novo 20p13-->p12.3 deletion in a patient with severe growth deficit.
We report on a small de novo interstitial deletion of the short arm of chromosome 20, 46,XY,del(20)(p12.3p13), in a young boy with hypotonia, moderate development delay, mild facial dysmorphism and severe growth failure. This patient did not show major features of Alagille-Watson Syndrome (AWS) which are common in more proximal 20p deletions. Standard and high resolution chromosome banding analysis revealed an apparent terminal deletion. Nevertheless, using chromosomal fluorescent in situ hybridization (FISH) and molecular analysis with polymorphic markers, we demonstrated that the abnormal chromosome resulted from a de novo interstitial deletion of paternal origin spanning from D20S842 to D20S900 and covering approximately 6 Mb. These findings indicate that a karyotype can lead to insufficient characterization of an apparently terminal deletion, and that one or a few genes in 20p13-->p12.3 bands are important for normal growth.
Alleles↗
Genetics of pathways regulating body weight in the development of obesity in humans.
Although rapid globalization of the Westernized way of life is responsible for the large rise in the number of obesity cases (about 1 billion individuals are now overweight or frankly obese), obesity is a typical common multifactorial disease in that environmental and genetic factors interact, resulting in a disease state. There is strong evidence for a genetic component to human obesity: e.g., the familial clustering (the relative risk among siblings being 3-7) and the high concordance of body composition in monozygotic twins. However, the role of genetic factors in many human obesities (referred to as "common obesity" in this review) is complex, being determined by interaction of several genes (polygenic), each of which may have relatively small effects (i.e., they are "susceptibility" genes and work in combination with each other as well as with environmental factors such as nutrients, physical activity, and smoking).
Adipocytes↗