Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Gilbert's syndrome is a mild hereditary unconjugated hyperbilirubinemia caused by mutations in the bilirubin UDP-glucuronosyltransferase gene (UGT1A1). The causative mutation in Caucasians is almost exclusively a TA dinucleotide insertion in the TATA box of the UGT1A1 promoter. Affected individuals are homozygous for the variant promoter and have 7 instead of 6 TA repeats. The aim of the present study was to determine the genotypes of UGT1A1(TA)n promoter polymorphism in the healthy Slovenian population and to investigate the association of genotypes with serum bilirubin levels. 236 healthy subjects were genotyped by single-strand conformation polymorphism analysis, which was validated by sequence analysis. The frequencies of genotypes were as follows: (TA)(6/6) (38.1%), (TA)(6/7) (47.9%), (TA)(7/7) (13.6%). There was a statistically significant association of genotypes with serum bilirubin levels (p<0.001). Subjects with genotype (TA)(7/7) had the highest and subjects with genotype (TA)(6/6) the lowest total serum bilirubin levels. One individual in the group had the rare genotype (TA)(7/8) (0.4%). Analysis of his family showed the following genotypes: (TA)(6/8) in his father and sister and (TA)(7/8) in his two brothers. In conclusion, the frequency of UGT1A1(TA)n promoter polymorphism genotypes was determined for the first time in the Slovenian population and is similar to frequencies observed in other Caucasian populations. The extremely rare (TA)8 allele in Caucasians was found also in Slovenians.
Blood Cells Mol Dis
PMID:UGT1A1(TA)n promoter polymorphism--a new case of a (TA)8 allele in Caucasians. 1719 9

Many intron positions are conserved in varying subsets of eukaryotic genomes and, consequently, comprise a potentially informative class of phylogenetic characters. Roy and Gilbert developed a method of phylogenetic reconstruction using the patterns of intron presence-absence in eukaryotic genes and, applying this method to the analysis of animal phylogeny, obtained support for an Ecdysozoa clade (Roy SW, Gilbert W. 2005. Resolution of a deep animal divergence by the pattern of intron conservation. Proc Natl Acad Sci USA. 102:4403-4408). The critical assumption in the method was the independence of intron loss in different branches of the phylogenetic tree. Here, this assumption is refuted by showing that the branch-specific intron loss rates are strongly correlated. We show that different tree topologies are obtained, in each case with a significant statistical support, when different subsets of intron positions are analyzed. The analysis of the conserved intron positions supports the Coelomata topology, that is, a clade comprised of arthropods and chordates, whereas the analysis of more variable intron positions favors the Ecdysozoa topology, that is, a clade of arthropods and nematodes. We show, however, that the support for Ecdysozoa is fully explained by parallel loss of introns in nematodes and arthropods, a factor that does not contribute to the analysis of the conserved introns. The developed procedure for the identification and analysis of conserved introns and other characters with minimal or no homoplasy is expected to be useful for resolving many hard phylogenetic problems.
Mol Biol Evol 2007 Nov
PMID:Support for the Coelomata clade of animals from a rigorous analysis of the pattern of intron conservation. 1789

PCR products can be sequenced using either the dideoxy (Sanger) or chemical (Maxam-Gilbert) approaches. In the dideoxy methods presented here, the target sequence is amplified and an excess of one strand of the target sequence (relative to its complement) is then generated by "asymmetric PCR," where one primer is present in vast excess over the other. This single-stranded product serves as the template for conventional dideoxy sequencing methods. Another procedure prepares PCR products for use as templates fes for characterizing unlabeled product by genomic sequencing and chemical sequencing of end-labeled products are also presented.
Curr Protoc Mol Biol 2001 Nov
PMID:Direct DNA sequencing of PCR products. 1826 16

Recently, a new phylogenetic method employing intron position sharing across species was proposed and support for a Coelomate clade reported (Zheng et al. 2007. A rigorous analysis of the pattern of intron conservation supports the Coelomata clade of animals. Mol Biol Evol. 24:2583-2592.). Here, we show that the previous analysis depends on: 1) an idiosyncratic definition of "conserved" introns, 2) exclusion of all phylogenetically informative introns present in outgroups, 3) incorrect inference of change along the critical branch, and 4) lack of variation in rates across branches. The method thus seems unlikely to give accurate results. In addition, we address differences in rates of loss across intron sites, which Zheng et al. claimed invalidates our previous analysis that supported Ecdysozoa (Roy and Gilbert. 2005a. Resolution of a deep animal divergence by the pattern of intron conservation. Proc Natl Acad Sci USA. 102:4403-4408.). Instead, we show that our conclusions are likely to be robust to such concerns.
Mol Biol Evol 2008 Apr
PMID:Rare genomic characters do not support Coelomata: intron loss/gain. 1828 Dec 72

Gilbert's syndrome causes mild, unconjugated hyperbilirubinemia and is present in approximately 10% of the Caucasian population. The basis of the disorder is a 70% reduction in bilirubin glucuronidation catalyzed by the UDP-glucuronosyltransferase 1A1 (UGT1A1), which, in Caucasians, is the result of a homozygous TA insertion into the promoter region of the UGT1A1 gene (UGT1A1*28). Homozygous carriers of UGT1A1*28 as well as those with additional UGT1A variants can suffer from severe irinotecan toxicity or jaundice during treatment with the protease inhibitor atazanavir. UGT1A1*28 genotyping identifies patients at risk for drug toxicity and can increase drug safety by dose individualization. Rapid and facile UGT1A1*28 genotyping is therefore of great clinical importance. Two hundred ninety-one patients with suspected Gilbert's syndrome were genotyped using the TaqMan 5'nuclease assay with minor groove binder-non fluorescent quench probes; results were confirmed by direct sequencing. Ninety-six patients (33%) were homozygous for UGT1A1*28, which was verified by direct sequencing of a different PCR product showing 100% concordance with the TaqMan PCR results. We describe a novel UGT1A1*28 genotyping method that employs allelic discrimination by TaqMan PCR. This assay provides a rapid, high-throughput, and cost-effective method for Gilbert's syndrome genotyping, which is of value for pretreatment screening of potential irinotecan toxicity. The method utilizes a technological platform that is widely used in clinical practice and could therefore be easily adapted for routine clinical applications.
J Mol Diagn 2008 Nov
PMID:Rapid allelic discrimination by TaqMan PCR for the detection of the Gilbert's syndrome marker UGT1A1*28. 1883 63

DNA sequences extracted from ancient remains are increasingly used to generate large population data sets, often spanning tens of thousands of years of population history. Bayesian coalescent methods such as those implemented in the software package BEAST can be used to estimate the demographic history of these populations, sometimes resulting in complex scenarios of fluctuations in population size, which can be correlated with the timing of environmental events, such as glaciations. Recently, however, Axelsson et al. (Axelsson E, Willerslev E, Gilbert MTP, Nielsen R. 2008. The effect of ancient DNA damage on inferences of demographic histories. Mol Biol Evol 25:2181-2187.) claimed that many of these complex demographic trends are likely to be the result of postmortem DNA damage, a problem that they investigate by removing all sites involving transitions from ancient sequences prior to analysis. When this solution is applied to a previously published data set of Pleistocene bison, they show that the demographic signal of population expansion and decline disappears. Although some apparently segregating mutations in ancient sequences may be due to postmortem damage, we argue that discarding the data will result in loss of power to detect patterns of population change. Instead, to accommodate this problem, we implement a model in which sequences are the result of a joint process of molecular evolution and postmortem DNA damage within a probabilistic inference framework. Through simulation, we demonstrate the ability of this model to accurately recover evolutionary parameters, demographic history, and DNA damage rates. When this model is applied to the bison data set, we find that the rate of DNA damage is significant but low and that the reconstruction of population size history is nearly identical to previously published estimates.
Mol Biol Evol 2009 Feb
PMID:Accommodating the effect of ancient DNA damage on inferences of demographic histories. 1900 34

We investigated the hypothesis that coinheritance of the common A(TA)(n)TAA promoter mutation at the UGT1A1 locus associated with Gilbert syndrome is a risk factor for gallstone formation in a homogeneous adult population, by conducting a case-control study that included 198 adult patients with cholelithiasis and 152 healthy controls both of Greek origin. Three genotypes were found: 7/7 (17.8% in controls and 23.3% in patients), 6/7 (33.5% in controls and 46.5% in patients), and normal homozygous 6/6 (48.7% in controls and 30.3% in patients). The Gilbert UGT1A1 genotypes 6/7 and 7/7 show significant association (odds ratio 2.225, 95% confidence interval 1.373-3.605, p=0.001, and odds ratio 2.101, 95% confidence interval 1.171-3.770, p=0.013, respectively) with cholelithiasis risk. This association supports the theory that genetic factors are responsible for a fraction of symptomatic gallstone disease; however, further studies are required in different ethnic groups to fully elucidate the involvement of Gilbert syndrome in gallstone disease.
Genet Test Mol Biomarkers 2009 Feb
PMID:Gilbert syndrome as a predisposing factor for cholelithiasis risk in the Greek adult population. 1930 88

Recent experimental study [S.D. Gilbert, S.J. Mediatore, R.T. Batey, Modified pyrimidine specifically bind the purine riboswitch, J. Am. Chem. Soc. 128 (2006) 14214-14215] demonstrated that the purine riboswitch could specifically bind some ligands other than purines such as amino-pyrimidines, and the authors proposed that the five-membered ring of purine was not required for recognition. To get insight into the interaction details, we used molecular docking method to investigate the interactions of a mutant form of guanine riboswitch with a series of amino-purines, amino-pyrimidines and imidazole derivatives, and employed molecular simulation method to study the dynamic behavior of the selected complexes. The calculation results reveal that (1) all the amino-purines and amino-pyrimidines bind in a same cavity composed of four nucleobases including U22, U47, U51 and U74, which is consistent with the experimental results, while the two imidazole derivatives adopt other binding modes; (2) the purines are engulfed within three-way junction motifs, but most pyrimidines only form two-way junctions with the riboswitch; (3) the number and position of amino substituents could seriously affect the binding of pyrimidines. As riboswitches are potentially excellent candidates for antibiotic therapeutics, these findings may be useful for understanding the range of compounds that riboswitch can specifically recognize.
J Mol Graph Model 2009 Aug
PMID:Theoretical studies on the interaction of modified pyrimidines and purines with purine riboswitch. 1938 Feb 44

Atherosclerosis is a leading cause of morbidity and mortality. Oxidative stress is thought to play a role in its pathogenesis. Bilirubin is an endogenous antioxidant that is mildly elevated in people with Gilbert syndrome. Homozygosity for a A(TA)7TAA variant of the UDP-glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) promoter is necessary for expression of the Gilbert phenotype. We studied the relationship between coronary artery disease (CAD) and the Gilbert genotype. Decedents who underwent autopsy were categorized into none/mild, moderate, and severe CAD groups based on autopsy findings. Known CAD risk factors were evaluated for each decedent in the severe CAD group (n=35), and for an age, race, and sex-matched control group with none/mild CAD (n=45). Formalin-fixed paraffin-embedded (FFPE) tissue was tested for UGT1A1 promoter variants by polymerase chain reaction and capillary electrophoresis. To our knowledge, this is the first study to successfully apply UGT1A1 promoter genotyping to formalin-fixed paraffin-embedded tissue, which may facilitate more thorough examination of clinicopathologic correlations. The frequency of the Gilbert genotype was compared between the none/mild cohort and the severe cohort. UGT1A1 promoter genotype data were obtained for 76/80 cases. The overall frequency of the Gilbert genotype compared well with previously reported frequencies at 16%, with a frequency of 16% in the none/mild CAD group and 15% in the severe CAD group. These findings suggest that UGT1A1 promoter genotype is not a major factor contributing to risk of CAD.
Diagn Mol Pathol 2009 Dec
PMID:UGT1A1 promoter genotype is not strongly associated with severity of coronary artery disease. 1986 94

Organisms use proteins to perform an enormous range of functions that are essential for life. Proteins are usually composed of 20 different kinds of amino acids that each contain between one and four nitrogen atoms. In aggregate, the nitrogen atoms that are bound in proteins typically account for a substantial fraction of the nitrogen in a cell. Many organisms obtain the nitrogen that they use to make proteins from the environment, where its availability can vary greatly. These observations prompt the question: can environmental nitrogen scarcity lead to adaptive evolution in the nitrogen content of proteins? In this issue, Gilbert & Fagan (2011) address this question in the marine cyanobacteria Prochlorococcus, examining a variety of ways in which cells might be thrifty with nitrogen when making proteins. They show that different Prochlorococcus strains vary substantially in the average nitrogen content of their encoded proteins and relate this variation to nitrogen availability in different marine habitats and to genomic base composition (GC content). They also consider biases in the nitrogen content of different kinds of proteins. In most Prochlorococcus strains, a group of proteins that are commonly induced during nitrogen stress are poor in nitrogen relative to other proteins, probably reflecting selection for reduced nitrogen content. In contrast, ribosomal proteins are nitrogen rich relative to other Prochlorococcus proteins, and tend to be down-regulated during nitrogen limitation. This suggests the possibility that decaying ribosomal proteins act as a source of nitrogen-rich amino acids during periods of nitrogen stress. This work contributes to our understanding of how nutrient limitation might lead to adaptive variation in the composition of proteins and signals that marine microbes hold great promise for testing hypotheses about protein elemental costs in the future.
Mol Ecol 2011 Jan
PMID:How Prochlorococcus bacteria use nitrogen sparingly in their proteins. 2109 57


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