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At least 109 records · Page 6Linked to original sources
PubMed2006

A hepatocyte nuclear factor-4 alpha gene (HNF4A) P2 promoter haplotype linked with late-onset diabetes: studies of HNF4A variants in the Norwegian MODY registry.

Variants in hepatocyte nuclear factor (HNF)-4alpha cause maturity-onset diabetes of the young, type 1 (MODY1) and may also be risk factors for type 2 diabetes. We sequenced the HNF4A gene of 95 MODY3-negative probands from the Norwegian MODY Registry. We found three novel coding variants in exon 8 of HNF4A: G326R, T339I, and W340X. In intron 7, we noted a single nucleotide polymorphism in the binding site of a previously published primer pair, which in some cases caused allelic drop out when amplifying exon 8. We also detected two novel sequence variants of the P2 promoter region, of which P2 -192C>G showed linkage with diabetes in two families (maximal logarithm of odds score of 3.1 and 0.8, respectively). This variant and a surrounding haplotype restricted by 3.7 Mb was also found in two Danish MODY pedigrees. The age of onset was higher in the P2 -192C>G carriers (median 45 years) compared with that reported for other MODY1 individuals. We could not support a biological role of the P2 promoter variant by in vitro transfection assays. In conclusion, we have identified three novel HNF4A mutations and a 3.7-Mb haplotype, including the HNF4A P2 promoter, which was linked with diabetes.

Adult↗
PubMed1994

Six mutations in the glucokinase gene identified in MODY by using a nonradioactive sensitive screening technique.

We have reported that 56% of French families with maturity-onset diabetes of the young (MODY) carry a mutation in the glucokinase gene (GCK). Therefore, we have established a quick and sensitive nonradioactive technique (with the PhastSystem based on single-strand conformation polymorphism [SSCP] analysis) to routinely screen the 12 exons of GCK for mutations. We have studied GCK in 12 young hyperglycemic patients with a strong family history of type II diabetes. SSCP variants were observed in 6 of those 12 patients (50%), which cosegregated with diabetes in five families where DNA from additional members was available. Direct sequencing identified a 10-bp (base pair) deletion in exon 3; a 33-bp deletion at the exon 5/intron 5 junction, including the two consensus bases (GT) of the donor splice site; a nonsense mutation in exon 5 (Arg186-->Stop) in a Black-African family, which has been identified previously in a Caucasian family; and three missense mutations: Thr209-->Met209 in exon 6, Gly261-->Glu261 in exon 7, and Arg36-->Trp36 in exon 2. The missense mutation in exon 2 was found only in the second and third generation of the tested family but not in the first. To our knowledge, this is the first time that a de novo mutation of GCK is reported within a family. All six families carrying a mutation in GCK were typical MODY and most of their affected members had a mild form of diabetes. This nonradioactive SSCP technique may be useful to routinely diagnose glucokinase deficiency, which is an important cause of hyperglycemia among young type II diabetic patients.

Adult↗
PubMed2002

[Clinical, biochemical and immunological characteristic of diabetes type I, LADA, diabetes type II, and MODY patients].

Right classification of diabetes is important clinical issue. The aim of present study was to compare clinical, biochemical and immunological features, to analyze their practical use and to establish new decision tree which make the distinction between diabetes type 1, LADA, diabetes type 2 and MODY. We studied 97 not obese (mean BMI 26.3 +/- 4.9 kg/m2) patients aged 14 to 70 years, mean age 43 +/- 11.7 years, 53 women, 44 men. Mean duration of diabetes--2.3 +/- 4.3 years. We measured basal and stimulated C-peptide (6 minutes after 1 mg i.v. glucagon) (ELISA) and antibodies titers to glutamic acid decarboxylase--antiGAD65, tyrosine phosphatase-like molecule--IA2 and insulin--IAA (RIA). Autoimmune diabetes (LADA, type 1) was diagnosed with presence of one or more islet antigen antibodies. The highest frequencies had anti-GAD antibodies 33/97 (34%). The most complicated was to sort out group of patients with LADA. Comparison between this group and patients with diabetes type 2 have shown that BMI, co-existence of autoimmune disease, autoimmune markers and basal and stimulated C-peptide level measured at entry for the classification were useful in differentiation. Moreover we observed significantly lower C-peptide basal, stimulated and over basal level in group with MODY diabetes in comparison to diabetes type 2 patients. In the studied group were 5 patients with diabetes type 2 and obesity, in relatively young age. At the end there was one case of ADM (atypical diabetes mellitus). Clinical criteria for the classification of diabetes not always correlated with diagnosis. Autoimmune markers, basal and stimulated C-peptide were useful specially in differentiation between LADA and diabetes type 2 or diabetes type 1. Autoimmune diabetes co-existe with autoimmune disease. Proposed diagnostic scheme take for consideration presence of autoantibodies as well as C-peptide criteria.

Adolescent↗
PubMed1997

[Maturity-onset diabetes of the young (MODY)--a heterogeneous disease picture].

A family with maturity-onset diabetes of the young (MODY), a rare subtype of non-insulin-dependent diabetes mellitus (NIDDM), is described. This familial form of diabetes is characterized by an early age of onset and an autosomal dominant inheritance. All three patients developed diabetes at an early age and were not obese. The diabetes was always well controlled and none of the patients developed late complications. The clinical and molecular-genetic characteristics of the different forms of MODY are described, as well as the diagnostic work-up and therapeutic management.

Adult↗
PubMed2001

[SSCP (single strand conformation polymorphism) analysis for detection of point mutations. A technique and its limits exemplified by dominantly inherited forms of diabetes (MODY)].

BACKGROUND: Molecular biological techniques of mutation detection become more and more a focus of interest in clinical medicine because the responsible genes are now known for an increasing number of diseases and the detection is essential to enable reliable predictions and to design individual therapies. Therefore the SSCP (Single Strand Conformation Polymorphism) analysis is one of the most commonly applied methods in detection of point mutations. SSCP ANALYSIS: The use of SSCP for detection of the pathogenic mutations of MODY (Maturity Onset Diabetes in the Young) is described as an example. Handling, efficiency and costs are critically analyzed. In a blind test, this method was only partly suitable for reliable analysis. Particularly diseases without a distinct hotspot and with a widespread distribution pattern of mutations throughout the coding sequence require sequencing as the gold standard.

DNA Mutational Analysis↗
PubMed2002

Identification of three new mutations of the HNF-1 alpha gene in Japanese MODY families.

AIM/HYPOTHESIS: We analysed Japanese MODY patients for mutations in the HNF-1 alpha gene. METHODS: Fifty unrelated Japanese patients with early-onset diabetes (diagnosed at 25 years of age or younger) or with a strong family history of diabetes were screened for mutations in the HNF-1 alpha gene. Functional studies of the mutant HNF-1alpha were carried out. RESULTS: We identified three new mutations in the HNF-1 alpha gene in the families with a strong family history for diabetes. One mutation (L518P519fsTCC --> A) was identified in three unrelated families, while the other two mutations (T521I and V617I) were identified in one family. We also identified the A site of the promoter (+102G-to-C), which was reported previously. We examined the functional properties of the mutant HNF-1alpha. By increasing the amount of L518P519fsTCC-->A-HNF-1alpha, increasing inhibition of the transcription of human transthyretin (TTR) was observed (up to 61% of the control). Increasing amounts of T521I-HNF-1alpha or V617I-HNF-1alpha mutant proteins increased TTR promoter transcription up to 4.3-fold and 2.4-fold, respectively, whereas both increased transcription up to 12.4-fold of the control. CONCLUSION/INTERPRETATION: The L518P519fsTCC --> A was identified for the first time and this mutation might be a common cause of Japanese MODY3 in Okinawa area. In addition, both the T521I and V617I mutations were present in two patients in the same family. Since the prevalence of these mutations is relatively high (10%, 5/50), the HNF-1 alpha gene needs to be screened for mutations in patients either with early-onset diabetes or with a strong family history for diabetes.

Adult↗
PubMed1992

A microsatellite polymorphism associated with the PLC1 (phospholipase C) locus: identification, mapping, and linkage to the MODY locus on chromosome 20.

A highly polymorphic (dC-dA)n.(dG-dT)n dinucleotide repeat at the PLC1 locus on human chromosome 20 has been identified. Primers flanking the dinucleotide repeat were used for PCR amplification of the repeat region in 37 informative kindreds from the Centre d'Etude du Polymorphisme Humain. Two-point linkage analysis indicates that PLC1 is closely linked to several chromosome 20 markers, including D20S16 (Zmax = 41.25; theta = 0.07), D20S17 (Zmax = 42.81; theta = 0.09), and ADA (Zmax = 57.24; theta = 0.05). Multipoint linkage analysis places the PLC1 locus between D20S18 and D20S17, 11.2 and 6.6 cM, respectively, from these loci (sex-averaged distances). In addition, the PLC1 gene shows linkage to the maturity-onset diabetes of the young (MODY) locus on chromosome 20 with a lod score of 4.57 at theta = 0.089.

Base Sequence↗
PubMedDate not supplied

CT colonography using different reconstruction modi.

OBJECTIVE: Performing computed tomography (CT) colonography, we compared different reconstruction modi for the detection of colorectal polyps. METHODS: The CT data of 48 patients using 16-slice helical CT were analysed in axial slices, virtual-endoscopy and colon-dissection modus. RESULTS: The sensitivity (specificity) for the detection of colonic polyps was 94% (80%) if using "colonic-dissection" tool and 89% (80%) if using "virtual-endoscopy" tool. The difference between the virtual endoscopy and colon dissection, considering polyps up to 4.9 mm, was significant. CONCLUSIONS: Reconstruction software colon dissection improves the sensitivity of CT colonography.

Colonic Polyps↗
PubMed2004

HNF-4alpha: from MODY to late-onset type 2 diabetes.

Maturity-onset diabetes of the young (MODY) is a rare subtype of type 2 diabetes that is characterized by autosomal-dominant inheritance and can be caused by mutations in hepatocyte nuclear factor 4alpha (HNF-4alpha). Odom and colleagues have combined chromatin immunoprecipitation with promoter microarrays to identify numerous promoters occupied by HNF-4alpha in the human liver and islet, suggesting a very broad role for HNF-4alpha in glucose homeostasis. This notion is supported by recent genetic studies linking HNF-4alpha to the much more common late-onset type 2 diabetes.

Adolescent↗
PubMed1980

[Autosomal dominant mild juvenile diabetes mellitus (MODY) (author's transl)].

A family is described in which eleven members, over four generations, suffer from the autosomal dominant inherited maturity onset type diabetes of young people (MODY). A comparison of these findings with those of six families previously described in the literature shows in particular that: 1. manifestation of the disease is predominantly at a fairly young age, 2. the complaint is not insulin-dependent nor is it progressive, 3. when medical supervision is adequate, there are hardly any secondary complications, 4. the inheritance pattern is autosomal dominant with high penetrance and probably a stronger expressivity in the female. This disease can be separated from the classical, insulin-dependent diabetes of the young, from the autosomal dominant lipatrophic diabetes and from the heterozygous form of the autosomal recessive complaint, which in the homozygous state shows diabetes mellitus and insipidus with optic atrophy.

Adolescent↗
PubMed2006

Examination of PPP1R3B as a candidate gene for the type 2 diabetes and MODY loci on chromosome 8p23.

The product of the PPP1R3B gene (G(L)) is the regulatory subunit of PP1 - a serine/threonine phosphatase involved in the modulation of glycogen synthesis in the liver and skeletal muscle. The PPP1R3B gene is located on chromosome 8p23 in a region that has been linked with type 2 diabetes and maturity-onset diabetes of the young (MODY). We examined whether sequence variants at the PPP1R3B locus are responsible for the linkage with diabetes observed at this location. RT-PCR analysis revealed the existence of two alternative promoters. These and the two exons of this gene were sequenced in the probands of 13 Joslin families showing the strongest evidence of linkage at 8p23. A total of 20 variants were observed: two in the 5' flanking region, one in the intron (9 bp 5' of exon 2), and 17 in the 3' UTR. The intronic variant generated a new acceptor splice site, resulting in an alternative splice variant with a longer 5' UTR. However, neither this nor other variants segregated with diabetes in the 13 'linked' families. Furthermore, allele frequencies were similar in 90 family probands from the Joslin Study and 347 unrelated controls. Thus, genetic variability in the PPP1R3B gene does not appear to contribute to diabetes in our mostly Caucasian families. However, a role cannot be excluded in other populations such as the Japanese, among whom linkage to diabetes is also observed at 8p23 and a non-synonymous mutation has been detected in the PPP1R3B gene.

5' Untranslated Regions↗
PubMed1995

Influence of different flow modi during extracorporeal circulation on endothelial-derived vasoactive substances.

Influences of shear stress on endothelin (ET) as well as prostacyclin (PGF) levels are common findings in different experimental settings. Thus, plasma levels of both substances seem to be a good tool to verify if different flow modi can be produced in blood vessels by generating pulsatile flow with a roller pump. In the present study, 20 patients scheduled for elective aortocoronary bypass operation were divided into two groups at random. One group was perfused with nonpulsatile (CON-group) and the other with pulsatile flow (PULS-group) during extracorporeal circulation. ET and PGF plasma levels were monitored perioperatively together with parameters of renal function and haemodynamic data. ET values were only slightly elevated at the end of extracorporeal circulation (mean baseline value; CON 3.1 pg/ml and PULS 3.2 pg/ml; mean maximal values at the end of cardiopulmonary bypass (CPB) 4.0 pg/ml and 3.9 pg/ml respectively). Prostacylin values (median baseline values: CON 56.7 pg/ml and PULS 57.1 pg/ml) peaked at the end of operation (median CON 117.8 pg/ml and PULS 137.5 pg/ml respectively) with a subsequent small decrease. No differences between the groups could be observed at any time point with respect to vasoactive substances, urine output (CON 6.5 ml/min and PULS 6.2 ml/min) or haemodynamics during CPB. This confirms studies emphasizing that no effective microvascular pulsatile flow is generated by conventional pulsatile flow-generating devices. In the present study, normothermia and a constant flow rate were maintained during CPB. Aortic cannulae (body-surface-related not maximal large diameters) were inserted. Altering these procedures may have led to more pronounced differences between the groups. All patients had an uneventful course after the operation. Similar to other reports, the present study was not able to demonstrate any benefit of pulsatile perfusion during extracorporeal circulation.

Aged↗
PubMed2004

Hepatocyte nuclear factor-1 alpha gene inactivation: cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the young (MODY)3 families.

Heterozygous germline mutations of the hepatocyte nuclear factor (HNF)-1 alpha are associated with maturity-onset diabetes of the young (MODY)3. Recently, the biallelic inactivation of the HNF-1 alpha gene was reported in liver adenomas. We show the occurrence of liver adenomatosis in six MODY3-affected patients from two unrelated and large families. Liver adenomatosis was characterized by the presence of numerous adenomas within a normal hepatic parenchyma. The HNF-1 alpha hot-spot germline mutation P291fs was identified in the two probands and in 16 relatives from the two families. The six patients affected by liver adenomatosis and diabetes exhibited the mutation. The analysis of liver-cell tumors from two affected patients evidenced the biallelic inactivation of HNF-1 alpha. The familial screening confirmed the clinical heterogeneity of the liver phenotype, from silent liver adenomatosis to fatal hemorrhage. These observations warrant the systematic screening for liver adenomatosis in MODY3 families to prevent its potentially deadly complications. Moreover, such screening may help to determine if a particular mutational spectrum of HNF-1 alpha is associated with liver adenomatosis and to establish its prevalence in this frequent form of diabetes in the young adult.

Adenoma↗
PubMed2006

Application of SEBAL approach and MODIS time-series to map vegetation water use patterns in the data scarce Krishna river basin of India.

Evapotranspiration (ET) from irrigated land is one of the most useful indicators to explain whether the water is used as "intended". In this study, the Surface Energy Balance Algorithm for Land (SEBAL) was used to compute actual ET from a Landsat7 image of December 29, 2000 for diverse land use in the Krishna Basin in India. SEBAL ETa varies between 0 to 4.7 mm per day over the image and was quantified for identified land use classes. Seasonal/annual comparison of ETa from different land uses requires time series images, processed by SEBAL. In this study, the Landsat-derived snapshot SEBAL ETa result was interpreted using the cropping calendar and time series analysis of MODIS imagery. The wastewater irrigated area in the basin has the highest ETa in the image, partly due to its advanced growth stage compared to groundwater-irrigated rice. Shrub and forests in the senescence phase have similar ETa to vegetable/cash crops, and ETa from grasslands is a low 0.8 mm per day after the end of the monsoon. The results indicate that wastewater irrigation of fodder and rice is sufficient to meet crop water demand but there appears to be deficit irrigation of rice using groundwater.

Algorithms↗
PubMed1997

Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and early-onset NIDDM: evidence for a mutational hotspot in exon 4.

We have recently shown that mutations in the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1alpha are the cause of one form of maturity-onset diabetes of the young (MODY3). Here, we report the exon-intron organization and partial sequence of the human HNF-1alpha gene. In addition, we have screened the ten exons and flanking introns of this gene for mutations in a group of 25 unrelated white subjects from Germany who presented with NIDDM before 35 years of age and had a first-degree relative with NIDDM. Mutations were identified in nine of these individuals, suggesting that mutations in the HNF-1alpha gene are a common cause of diabetes in German subjects with early-onset NIDDM and a family history of diabetes. Thus, screening for mutations in this gene may be indicated in subjects with early-onset NIDDM. Interestingly, three of the nine mutations occurred at the same site in exon 4 with insertion of a C in a polyC tract, centered around codon 290 (designated Pro291fsinsC), thereby resulting in a frameshift during translation and premature termination. Analyses of linked DNA polymorphisms in the HNF-1alpha gene indicated that the Pro291fsinsC mutation was present on a different haplotype in each subject, implying that the polyC tract represents a mutational hot spot. We have also identified the mutation in the HNF-1alpha gene in the Jutland pedigree, one of the original MODY pedigrees reported in the literature, as being a T-->G substitution in codon 241, resulting in the replacement of a conserved Cys by Gly (C241G). The information on the sequence of the HNF-1alpha gene and its promoter region will facilitate the search for mutations in other subjects and studies of the role of the gene in determining normal beta-cell functions.

Adolescent↗
PubMed2001

["MODY" diabetes. Beyond a monogenic disease].

Maturity Onset Diabetes of the Young is a particular form of type 2 diabetes, classically defined by an autosomal dominant inheritance, a young age at diagnosis (before 25 years) and an insulin secretion defect. At this time, six MODY genes have been described. Beyond the apparent simplicity, the study of such monogenic model of disease may help us to approach a complex disease such as type 2 diabetes, where is involved to conserve a genetic and environmental factors network. This different approach may help us to better understand type 2 diabetes physiopathology.

Adolescent↗
PubMed2002

Mitochondrial diabetes, diabetes and the thiamine-responsive megaloblastic anaemia syndrome and MODY-2. Diseases with common pathophysiology?

Diabetes represents a conglomerate of diseases with chronic hyperglycaemia as hallmark. The present review discusses those diabetic cases that associate with variants in genes that affect the magnitude of the glycolytic flux and oxidative disposal of glucose by mitochondria in pancreatic beta-cells. These genetic variants result in an attenuated secretion of insulin in response to glucose stimulation. The diabetic states that associate with these genetic variants are MODY 2, thiamine responsive anaemia syndrome (TRAS) and mitochondrial diabetes. These disease states highlight the critical contribution of the carbohydrate flux through glycolysis and mitochondria and its coupling to ATP production in determining insulin secretion.

Anemia, Megaloblastic↗
PubMed1989

[Insulin and peptide C secretion after food ingestion and the interaction of insulin with its erythrocyte receptor in a family with MODY type diabetes mellitus].

In 12 members of a family with MODY, insulin and C-peptide release after intake of a test breakfast was measured as well as binding of insulin to its erythrocyte receptor. According to serum glucose concentrations, subjects were classified into: diabetic, carbohydrate intolerant, and normal subjects. The two diabetic patients had an insulin release pattern similar to that of non-insulin dependent diabetics. The two patients with carbohydrate intolerance presented hyperinsulinism either at base state and after stimulation. Of the eight normal subjects, three presented high concentrations of serum insulin either at base level and after stimulation; in the remaining five, base insulinemia was normal and the response after food intake was poor. Insulin binding to the receptor was decreased in diabetic patients and this anomaly was more evident in patients with carbohydrate intolerance. In the three patients with increased serum insulin concentration, no disturbances in insulin-receptor binding were detected; in the remaining five patients, insulin-receptor binding was significantly decreased. Our findings prove that these subjects present a disturbance of insulin release and an impairment of insulin-receptor binding with a predominance of one or the other alteration even before hyperglycemia is evident.

Adolescent↗