Identification of seven novel nucleotide variants in the hepatocyte nuclear factor-1? (TCF1) promoter region in MODY patients

Godart, François; Bellanné‐Chantelot, Christine; Clauin, Séverine; Gragnoli, Claudia; Abderrahmani, Amar; Blanché, Hélène; Boutin, Philippe; Chèvre, Jean-Claude; Froguel, Philippe; Bailleul, Bernard

doi:10.1002/(sici)1098-1004(200002)15:2<173::aid-humu6>3.0.co;2-w

Cited by 39 publications

(40 citation statements)

References 39 publications

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“…Similarly, changes in the number of tandem repeats in the 5'UTR of the P450 prostacyclin synthase gene CYP8A1 cause differences in its transcriptional activity, thereby moderating inflammatory processes (Chevalier et al 2001). Moreover, rare variant chromosomes with single base changes in the promoter of the hepatocyte nuclear factor-1α that decrease transcriptional activities have been found in families with monogenic diabetes (Godart et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Common variations in noncoding regions of the human natriuretic peptide receptor A gene have quantitative effects

et al. 2003

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Genetic susceptibility to common conditions, such as essential hypertension and cardiac hypertrophy, is probably determined by various combinations of small quantitative changes in the expression of many genes. NPR1, coding for natriuretic peptide receptor A (NPRA), is a potential candidate, because NPRA mediates natriuretic, diuretic, and vasorelaxing actions of the nariuretic peptides, and because genetically determined quantitative changes in the expression of this gene affect blood pressure and heart weight in a dose-dependent manner in mice. To determine whether there are common quantitative variants in human NPR1, we have sequenced the entire human NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript NPR1 gene and identified 10 polymorphic sites in its non-coding sequence by using DNA from 34 unrelated human individuals. Five of the sites are single nucleotide polymorphisms; the remaining five are length polymorphisms, including a highly variable complex dinucleotide repeat in intron 19. There are three common haplotypes 5' to this dinucleotide repeat and three 3' to it, but the 5' haplotypes and 3' haplotypes appear to be randomly associated. Transient expression analysis in cultured cells of reporter plasmids with the proximal promoter sequences of NPR1 and its 3' untranslated regions showed that these polymorphisms have functional effects. We conclude that common NPR1 alleles can alter expression of the gene as much as two-fold and could therefore significantly affect genetic risks for essential hypertension and cardiac hypertrophy in humans.

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Section: Discussionmentioning

confidence: 99%

Common variations in noncoding regions of the human natriuretic peptide receptor A gene have quantitative effects

et al. 2003

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“…Whereas the HNF-1a ±58 A ® C mutation is located in the promoter and affects gene transcription [8,10], the other three mutations are located in the coding region. The W113X HNF-1a mutation causes a premature transcriptional stop at amino acid 113 leading to a protein retaining the amino-terminal dimerization domain without either a DNA binding domain or a transactivation domain.…”

Section: Discussionmentioning

confidence: 99%

“…The NM unaffected Italy-1 family members have an average BMI of 21.31 kg/m 2 thus excluding that high basal insulin levels are secondary to obesity. Higher basal insulin concentrations might be the result of an initial beta-cell functional compensation in the NM Italy-1 members due to the HNF1a gene haploinsufficiency [10]; therefore NM Italy-1 members are probably better compensated at an earlier stage of disease, compared to MODY3 patients carrying mutations with dominant/negative effects. The C-peptide responses of MODY3 and MODY2 patients after glucagon stimulation, (values > 0.6 nmol/l) indicate the presence of residual beta-cell function, excluding misdiagnosis for Type I diabetes.…”

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Early-onset Type II diabetes mellitus in Italian families due to mutations in the genes encoding hepatic nuclear factor 1α and glucokinase

et al. 2001

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Maturity-onset diabetes of the young (MODY), a monogenic subset of Type II (non-insulin-dependent) diabetes mellitus, is caused by mutations in at least five different genes: HNF-4a-MODY1 [1], GCK-MODY2 [2], HNF-1a-MODY3 [3], IPF-1-MODY4 [4], and HNF-1b-MODY5 [5]. MODYis an autosomal dominant disorder with an onset typically under 25 years of age, and usually accounts for 2 % to 5 % of all patients with Type II diabetes but a true estimate is challenging because patients with MODY are often wrongly diagnosed as having Type I or Type II diabetes. Late-onset Type II diabetes is a polygenic heterogeneous disorder whose pathogenesis is not clear. We regard Type II diabetes as a genetically continuous spectrum of early-onset to late-onset diabetes, partially due to mutations in the MODY genes. The prevalence of HNF-1a, GCK and HNF-4a mutations in MODY patients varies among different populations. Up to now four missense mutations in the MODY2 [6,7] and none in the MODY3 gene have been identified in Italian MODY patients. The aim of our study Diabetologia (2001) AbstractAims/hypothesis. Maturity-onset-diabetes of the young (MODY) is caused by mutations in at least five different genes. Our aim was to determine the prevalence of the most common MODY genes in Italian families with early-onset Type II (non-insulin-dependent) diabetes mellitus. Methods. We screened 28 Italian early-onset Type II diabetic families (diagnosis < 35 years) for mutations in the hepatic nuclear factor-4a, (MODY1), glucokinase (MODY2) and hepatic nuclear factor-1a (MODY3). Both strands of exons, flanking introns and minimal promoter regions of the above-mentioned genes were amplified using polymerase chain reaction and were sequenced directly. Results. We identified four different mutations, three of which are not described, (W113X, G42P43fsCC ® A, H514R) and four new polymorphisms (G184G, T513T, IVS3-nt47delG, IVS1-nt53C ® G) in the hepatic nuclear factor-1a gene, two new potential mutations (G44S, IVS4nt + 7C ® T) and three new polymorphisms (promoter-nt84C ® G, IVS9 + nt8C ® T, IVS9 + nt49G ® A) in the glucokinase gene, and a new polymorphism (IVS1c-nt11T ® G) in the hepatic nuclear factor-4a gene. Conclusion/interpretation. Mutations in the hepatic nuclear factor-1a and glucokinase are associated with Type II diabetes in 14 % and 7 % of Italian families, respectively. Our findings provide an impetus for screening Italian MODY and early-non Type II diabetic families for mutations in the above mentioned genes to identify relatives at risk who could benefit from primary prevention care. [Diabetologia (2001) 44: 1326±1329]Keywords Type II diabetes mellitus, genetics, hepatocyte nuclear factor-1a, hepatocyte nuclear factor-4a, glucokinase, MODY, Italian, mutation, polymorphism. Corresponding author: C. Gragnoli, Molecular Endocrinology, WEL 320, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA E-mail: cgragnoli@partners.org Abbreviations: HNF, hepatocyte nuclear factor; GCK, glucokinase; IPF-1, insulin promoter factor-1...

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“…We have 174 sib‐pairs with T2D, 29 sib‐pairs/families with early‐onset T2D and MODY, whose proband had an onset of diabetes before 40 years of age. Among the 29 sib‐pairs/families with early‐onset T2D, seven have an already identified mutation in a MODY gene: four of these identified in MODY3 and two in MODY2 (Gragnoli et al, 1997, 2001; Godart et al, 2000) and one in MODY4 (Gragnoli et al, 2005b). …”

Section: Methodsmentioning

confidence: 99%

Squamous cell carcinoma of the nasal vestibule 1993–2002: A nationwide retrospective study from DAHANCA

et al. 2009

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Identification of seven novel nucleotide variants in the hepatocyte nuclear factor-1? (TCF1) promoter region in MODY patients

Cited by 39 publications

References 39 publications

Common variations in noncoding regions of the human natriuretic peptide receptor A gene have quantitative effects

Common variations in noncoding regions of the human natriuretic peptide receptor A gene have quantitative effects

Early-onset Type II diabetes mellitus in Italian families due to mutations in the genes encoding hepatic nuclear factor 1α and glucokinase

Squamous cell carcinoma of the nasal vestibule 1993–2002: A nationwide retrospective study from DAHANCA

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