Isolation and characterization of the human Gs alpha gene.

Kozasa, Tohru; Itoh, Hiroshi; Tsukamoto, Tatsuro; Kaziro, Yoshito

doi:10.1073/pnas.85.7.2081

Cited by 364 publications

(221 citation statements)

References 42 publications

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“…12 The promoter region of the ␣ s gene has been sequenced and characterized. 35 Its GC-content is extremely high (85%). Several GC-boxes but no typical TATA-or CAAT-boxes have been found identifying it as a typical 'housekeeping' gene.…”

Section: Discussionmentioning

confidence: 99%

Abnormal G protein αs- and αi2-subunit mRNA expression in bipolar affective disorder

et al. 1998

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Disturbances of events associated with intracellular signaling pathways have been suspected of involvement in the development or progression of affective disorders. Often, heterotrimeric G proteins are located at the beginning of these pathways as modulators of extracellular messages. For this reason, messenger RNA expression of three G protein ␣-subunits and of phosphatidylinositol-3 kinase (PI-3 K) regulatory subunit p85 was examined in granulocytes from patients with bipolar or unipolar affective disorder and compared to healthy controls. Messenger RNA expression of the G protein subunit ␣ q and of p85 was identical in unipolar and bipolar patients and in controls. Furthermore, mRNAs of G protein subunits ␣ s and ␣ i2 were not different in unipolar patients as compared to healthy controls. Alpha s mRNA, however, was markedly increased in bipolar patients. This increase was observed in lithiumtreated (more than 12 months) and in unmedicated patients. Elevated levels of ␣ i2 mRNA in unmedicated bipolar patients did not reach statistical significance, whereas mRNA in bipolar patients receiving lithium was significantly above controls. Finally, long-term medication of unipolar patients with lithium had no influence on ␣ i2 mRNA levels. The data reveal elevated mRNA levels of G␣ s as a robust feature of bipolar affective disorder. Moreover, despite responsiveness of ␣ i2 gene expression to cAMP-related events, no substantial upregulation of ␣ i2 mRNA was observed in bipolar patients. The lack of ␣ i2 mRNA upregulation, hence, could be an additional abnormality in these patients. Even though lithium was able to reinstate this upregulation, there was no feedback downregulation of ␣ s . This strongly supports the notion of major disturbances of the cAMP signaling system in bipolar illness.

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Section: Discussionmentioning

confidence: 99%

Abnormal G protein αs- and αi2-subunit mRNA expression in bipolar affective disorder

et al. 1998

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“…S1). The most downstream alternative first exon is Gαs exon 1, which generates transcripts encoding the ubiquitously expressed Gαs (6). The Gαs promoter resides within a nonmethylated CpG island, but despite the absence of differential methylation at its promoter, Gαs shows predominantly maternal expression in some tissues, including pituitary, thyroid, renal proximal tubules, and gonads (7-10); Gαs expression is biallelic in most other tissues (11)(12)(13).…”

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confidence: 99%

Loss of XLαs (extra-large αs) imprinting results in early postnatal hypoglycemia and lethality in a mouse model of pseudohypoparathyroidism Ib

Fernández-Rebollo

Maeda²,

Reyes³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Maternal deletion of the NESP55 differentially methylated region (DMR) (delNESP55/ASdel3-4 m , delNAS m ) from the GNAS locus in humans causes autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib delNASm ), a disorder of proximal tubular parathyroid hormone (PTH) resistance associated with loss of maternal GNAS methylation imprints. Mice carrying a similar, maternally inherited deletion of the Nesp55 DMR (ΔNesp55 m ) replicate these Gnas epigenetic abnormalities and show evidence for PTH resistance, yet these mice demonstrate 100% mortality during the early postnatal period. We investigated whether the loss of extralarge αs (XLαs) imprinting and the resultant biallelic expression of XLαs are responsible for the early postnatal lethality in ΔNesp55 m mice. First, we found that ΔNesp55 m mice are hypoglycemic and have reduced stomach-to-body weight ratio. We then generated mice having the same epigenetic abnormalities as the ΔNesp55 m mice but with normalized XLαs expression due to the paternal disruption of the exon giving rise to this Gnas product. These mice (ΔNesp55 m /Gnasxl m+/p− ) showed nearly 100% survival up to postnatal day 10, and a substantial number of them lived to adulthood. The hypoglycemia and reduced stomach-to-body weight ratio observed in 2-d-old ΔNesp55 m mice were rescued in the ΔNesp55 m / Gnasxl m+/p− mice. Surviving double-mutant animals had significantly reduced Gαs mRNA levels and showed hypocalcemia, hyperphosphatemia, and elevated PTH levels, thus providing a viable model of human AD-PHP-Ib. Our findings show that the hypoglycemia and early postnatal lethality caused by the maternal deletion of the Nesp55 DMR result from biallelic XLαs expression. The double-mutant mice will help elucidate the pathophysiological mechanisms underlying AD-PHP-Ib.stimulatory G protein | renal proximal tubule | cyclic AMP

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“…and consists of 13 exons and 12 introns. 17 Jia et al 18 identified a common silent single nucleotide polymorphism (SNP) in exon 5, T393C, without an exchange of amino acids. They described an association of this polymorphism with hypertension and response to betablocker therapy.…”

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confidence: 99%

Gender‐dependent association of the GNAS1 T393C polymorphism with early aseptic loosening after total hip arthroplasty

Bachmann

Hanenkamp

Kornacki

et al. 2008

Journal Orthopaedic Research

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The G-protein Gas is involved in the physiology and pathophysiology of bone. Especially, Gas is a key regulator of interleukin-6, which is a potent promoter of aseptic loosening. We hypothesized that the common single nucleotide polymorphism GNAS1 T393C could also affect time to aseptic loosening. Caucasian patients were genotyped for the GNAS1 T393C polymorphism. Time and median time to aseptic loosening were analyzed for dependency on GNAS1 genotypes. Time and median time were not significantly associated with genotypes. Additional analysis corrected for gender revealed, that the TT genotype was associated with significantly longer time (p ¼ 0.048) as well as median time ( p ¼ 0.022) to aseptic loosening in female patients. In contrast to the findings in females, male TT genotype carriers had significantly shorter time ( p ¼ 0.018) and median time ( p ¼ 0.023) to aseptic loosening. Compared with TT genotype carriers heterozygous patients had a 6.25-fold lower risk with a hazard ratio of 0.160 ( p ¼ 0.016) and male patients carrying the CC genotype had an 11-fold lower risk with a hazard ratio of 0.088 ( p ¼ 0.006) in multivariate analysis. The present study suggests a significant gender-dependent role of the T393C polymorphism in aseptic loosening. The apparently contradictory results in women and men and the finding that the GNAS1 T393C genotype is an independent factor for time to aseptic loosening in male patients assigned this polymorphism as an interesting target for further investigations in bone diseases. ß

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Isolation and characterization of the human Gs alpha gene.

Abstract: The gene for Gsa (the a subunit of the guanine nucleotide-binding protein G.) was isolated from human genomic libraries using rat Gsa cDNA as a probe.

Cited by 364 publications

References 42 publications

Abnormal G protein αs- and αi2-subunit mRNA expression in bipolar affective disorder

Abnormal G protein αs- and αi2-subunit mRNA expression in bipolar affective disorder

Loss of XLαs (extra-large αs) imprinting results in early postnatal hypoglycemia and lethality in a mouse model of pseudohypoparathyroidism Ib

Gender‐dependent association of the GNAS1 T393C polymorphism with early aseptic loosening after total hip arthroplasty

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