The G protein β3 subunit 825T allele is a genetic marker for enhanced T cell response

Lindemann, Monika; Virchow, Sebastian; Ramann, Frank; Barsegian, Vahé; Kreuzfelder, E.; Siffert, Winfried; Müller, Norbert; Grosse‐Wilde, H.

doi:10.1016/s0014-5793(01)02339-0

Cited by 88 publications

(70 citation statements)

References 29 publications

(34 reference statements)

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“…This splice variant, which lacks 123 nucleotides, hypothetically gives rise to a protein with a deletion of 41 amino acids. By means of RT-PCR experiments, expression of this alternatively spliced mRNA variant was confirmed in B lymphoblasts (28), neutrophils (34), and T lymphocytes (13). While homozygous 825C allele carriers express only the wild-type gene product, homo-and heterozygous 825T allele carriers apparently express both wildtype G␤3 as well as G␤3-s mRNA.…”

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confidence: 91%

Effects of the G protein β3-subunit gene C825T polymorphism: should hypotheses regarding the molecular mechanisms underlying enhanced G protein activation be revised? Focus on “A splice variant of the G protein β3-subunit implicated in disease states does not modulate ion channels”

Siffert

2003

Physiological Genomics

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confidence: 91%

Effects of the G protein β3-subunit gene C825T polymorphism: should hypotheses regarding the molecular mechanisms underlying enhanced G protein activation be revised? Focus on “A splice variant of the G protein β3-subunit implicated in disease states does not modulate ion channels”

Siffert

2003

Physiological Genomics

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“…Due to their pivotal function in many cell types, variation in the genes encoding the subunits of G proteins has the potential to play a role in numerous clinical conditions. Specifically, investigators have studied possible associations of the frequent substitution of a C with a T nucleotide at position 825 in exon 10 in the gene encoding the G protein β3 subunit (GNB3), resulting in the silent Ser275Ser polymorphism, with hypertension [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] and related cardiovascular phenotypes [16][17][18][19][20][21][22], and with obesity [22][23][24][25], psychological syndromes [26][27][28], type 1 diabetes complications (nephropathy, retinopathy and neuropathy) [29,30], type 2 diabetes [13,22,31,32], cancer [33] and various immunological responses [34]. The 825C>T polymorphism is associated with the occurrence of a splice variant with an in-frame deletion of 41 amino acids (from exon 9) including the fourth of seven Trp-Asp repeats, each consisting of approximately 40 highly conserved amino acids, which normally form a β-propeller peptide structure [1].…”

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confidence: 99%

Studies of the association of the GNB3 825C>T polymorphism with components of the metabolic syndrome in white Danes

et al. 2005

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Aims/hypothesis: The 825C>T polymorphism in the gene encoding the G protein β3 subunit (GNB3) causes enhanced G protein activation and increased in vitro cell proliferation. This polymorphism is also repeatedly associated with an increased risk of hypertension and has been studied in relation to obesity with divergent results. Only a few association studies have investigated whether this polymorphism is related to type 2 diabetes or the metabolic syndrome. We estimated the impact of the GNB3 825C>T polymorphism in relatively large-scale association studies of common phenotypes of the metabolic syndrome. Materials and methods: The GNB3 825C>T polymorphism was genotyped in 7,518 white Danish subjects using mass spectrometry analysis of PCR products. Case-control studies were undertaken for obesity, hypertension, type 2 diabetes and the metabolic syndrome, and a meta-analysis including data from the present study and previous studies of hypertension was performed. Quantitative trait studies of metabolic variables were carried out in 4,387 glucose-tolerant subjects. Results: We observed minor differences in 825C>T genotype distributions for type 2 diabetes (CC/CT/TT 49/41/10% (control) vs 46/46/9% (cases), respectively, p=0.007); however, after correction for multiple testing, these were not statistically significant. No association was found with hypertension, obesity or the metabolic syndrome. Curiously, the T allele was associated with nominally lower systolic and diastolic blood pressure levels-a finding in contrast with most previous studies-but not with other metabolic variables. Meta-analysis demonstrated a high degree of heterogeneity between study populations of different ethnic origin. Although there was a tendency towards an increased risk of hypertension among 825T allele carriers, this was not statistically significant. Conclusions/interpretation: The present study suggests no major involvement of the GNB3 825C>T polymorphism in components of the metabolic syndrome.

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“…Furthermore, the 825T allele is associated with enhanced signal transduction in human cells and tissues such as B lymphoblasts, 6 neutrophils, 7 T lymphocytes, 8 and fat cells. 9 However, the biochemical and molecular mechanisms underlying these associations were not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

Quantification of allele-specific G-protein β3 subunit mRNA transcripts in different human cells and tissues by Pyrosequencing

Sun

Siffert

et al. 2004

Eur J Hum Genet

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The G-protein 825T allele is associated with altered drug responses while the underlying mechanism is not fully understood. Differential expression of transcripts from the C and T alleles could contribute to this process. The C825T polymorphism located in exon 10 is in close linkage disequilibrium with the A(À350)G promoter single nucleotide polymorphism (SNP) and the C1429T SNP and could therefore serve as a marker for allele-specific expression resulting from the promoter SNP. However, alternative splicing of exon 10 in 825T allele carriers may result in under-represented mRNA transcripts. We, therefore, established a novel method based on the Pyrosequencing technology to quantify allele-specific transcript expression and quantified the allelic variance of the C1429T polymorphism located in the 3 0 -untranslated region of GNB3. Validation of the method was performed using linear regression analysis of measured versus expected ratios of DNA mixed at different known concentrations as well as determining allelespecific mRNA expression of the partially imprinted IGF-2 gene. We genotyped the C1429T polymorphism of 83 samples derived from six different human tissues and cell lines and quantified mRNA transcripts from different alleles using heterozygous samples. No significantly different transcript amounts from the two alleles were found. There were also no significantly different transcript amounts associated with different G(À350)A genotypes (P40.05). As a result, we could show that Pyrosequencing provides a sensitive tool to quantify allele-specific transcript expression. Our data do not support the hypothesis that differential G-protein activity associated with the C825T SNP results from different transcript amounts associated with specific GNB3 genotypes.

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The G protein β3 subunit 825T allele is a genetic marker for enhanced T cell response

Cited by 88 publications

References 29 publications

Effects of the G protein β3-subunit gene C825T polymorphism: should hypotheses regarding the molecular mechanisms underlying enhanced G protein activation be revised? Focus on “A splice variant of the G protein β3-subunit implicated in disease states does not modulate ion channels”

Effects of the G protein β3-subunit gene C825T polymorphism: should hypotheses regarding the molecular mechanisms underlying enhanced G protein activation be revised? Focus on “A splice variant of the G protein β3-subunit implicated in disease states does not modulate ion channels”

Studies of the association of the GNB3 825C>T polymorphism with components of the metabolic syndrome in white Danes

Quantification of allele-specific G-protein β3 subunit mRNA transcripts in different human cells and tissues by Pyrosequencing

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