GNAS imprinting and pituitary tumors.

Evidence from in vitro studies and naturally occurring human diseases indicate that several endocrine cells, and particularly somatotrophs, recognize cAMP as a growth factor. Accordingly, mutations of the alpha subunit of the stimulatory G protein gene (GNAS) leading to the constitutive activation of adenylyl cyclase (the so-called gsp oncogene) have been found in a significant proportion of GH-secreting pituitary adenomas. GNAS maps within a complex region known to have more than one imprinted genes. Indeed, GNAS locus gives rise to several transcripts, all resulting from splicing of alternative first exons to exon 2 of the Gsalpha gene by a parent-specific methylation pattern of most of its different promoters. This complex tissue-specific imprinting control results in a near-exclusive expression of Gsalpha from the maternal allele in specific endocrine tissues, including the pituitary. Due to the monoallelic origin of Gsalpha in normal pituitary gsp mutations occur on a maternal allele in order to have a phenotypic effect in both sporadic GH-secreting adenomas and those associated with the McCune-Albright syndrome. Moreover, this imprinted expression pattern appears to be relaxed in the majority of tumors negative for gsp that show biallelic expression of Gsalpha transcript. Interestingly, the clinical phenotype of gsp negative tumors containing high levels of Gsalpha mRNA and protein is similar to that characterizing gsp positive tumors. Therefore, genetic and epigenetic alterations of the GNAS gene, with subsequent dysregulation of the cAMP pathway, appear, to date, the only molecular hallmark of most GH-secreting adenomas.

Mantovani G ，Lania AG ，Spada A 《-》

Parental origin of Gsalpha mutations in the McCune-Albright syndrome and in isolated endocrine tumors.

Mantovani G ，Bondioni S ，Lania AG ，Corbetta S ，de Sanctis L ，Cappa M ，Di Battista E ，Chanson P ，Beck-Peccoz P ，Spada A ... -  《-》

Somatotroph Tumors and the Epigenetic Status of the GNAS Locus.

Romanet P ，Galluso J ，Kamenicky P ，Hage M ，Theodoropoulou M ，Roche C ，Graillon T ，Etchevers HC ，De Murat D ，Mougel G ，Figarella-Branger D ，Dufour H ，Cuny T ，Assié G ，Barlier A ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Relevant cAMP-specific phosphodiesterase isoforms in human pituitary: effect of Gs(alpha) mutations.

Persani L ，Borgato S ，Lania A ，Filopanti M ，Mantovani G ，Conti M ，Spada A ... -  《JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM》

Gs alpha overexpression and loss of Gs alpha imprinting in human somatotroph adenomas: association with tumor size and response to pharmacologic treatment.

Gs alpha, the alpha-subunit of the heterotrimeric GTP-binding protein, is coded from the GNAS gene, which is imprinted in a tissue-specific manner. Gs alpha is paternally silenced in normal pituitary, but Gs alpha imprinting relaxation is found in some tumoral tissue. In addition, Gs alpha mRNA levels are high in some somatotroph adenomas not bearing the active Gs alpha mutant, the gsp oncogene. In this study, the impact of loss of imprinting on Gs alpha expression level and on tumoral phenotype has been investigated. We compared the expression and imprinting of 4 transcripts of GNAS locus (NESP55, XL alpha s, exon 1A, Gs alpha) of 60 somatotroph adenomas with those of 23 lactotroph adenomas. The paternal and maternal transcripts were quantified using allele-specific real-time PCR and FokI polymorphism. Moreover, the methylation of exon 1A DMR was analyzed. As is the case for the gsp oncogene, high Gs alpha expression in gsp- tumors was associated with smaller tumor size and better octreotide sensitivity. A strong imprinting relaxation (percentage of paternal Gs alpha expression >or=7.5%) was found only in gsp- tumors. The loss of Gs alpha imprinting was associated with a decrease in exon 1A mRNA expression. Unexpectedly, the methylation status of exon 1A DMR was not modified in relaxed tumors. Maternal Gs alpha mRNA level decreased with exon 1A level, and consequently the loss of Gs alpha imprinting did not induce the expected Gs alpha overexpression. Finally, XL alpha s mRNA level correlated with that of paternal Gs alpha and of NESP55 showing the complexity of gene regulation in the GNAS locus.

Picard C ，Silvy M ，Gerard C ，Buffat C ，Lavaque E ，Figarella-Branger D ，Dufour H ，Gabert J ，Beckers A ，Brue T ，Enjalbert A ，Barlier A ... -  《INTERNATIONAL JOURNAL OF CANCER》