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Parental Origin of G_s Mutations in the McCune-Albright Syndrome and in Isolated Endocrine Tumors

Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore IRCCS (G.M., S.B., A.G.L., S.C., P.B.-P, A.S.), 20122 Milan, Italy; Department of Pediatrics, University of Turin, Regina Margherita Children’s Hospital (L.d.S.), Turin, Italy; Bambino Gesù, Children’s Hospital (M.C.), Rome, Italy; Pediatric Department, Institute G. Gaslini, University of Genoa (E.D.B.), Genoa, Italy; and Service d’Endocrinologie et des Maladies de la Reproduction, Centre Hospitalier Universitaire Bicetre, Université Paris XI (P.C.), Le Kremlin-Bicetre, France

Address all correspondence and requests for reprints to: Prof. Anna Spada, Istituto di Scienze Endocrine-Padiglione. Granelli, Ospedale Maggiore IRCCS, Via Francesco Sforza 35, 20122 Milan, Italy. E-mail: anna.spada{at}unimi.it.

Activating mutations of the G_s gene are detected in different endocrine tumors, such as GH-secreting adenomas and toxic thyroid adenomas, and in hyperfunctioning glands from patients with McCune-Albright syndrome (MAS). There is increasing evidence that the G_s gene is subjected to imprinting control and that G_s imprinting plays a key role in the pathogenesis of different human diseases. The aim of this study was to investigate the presence of a parent specificity of G_s mutations in 10 patients affected with MAS and 12 isolated tumors (10 GH-secreting adenomas, one toxic thyroid adenoma, and one hyperfunctioning adrenal adenoma). The parental origin of G_s mutations was assessed by evaluating NESP55 and exon 1A transcripts, which are monoallelically expressed from the maternal and paternal alleles, respectively. By this approach, we demonstrated that in isolated GH-secreting adenomas, as well as in MAS patients with acromegaly, G_s mutations were on the maternal allele. By contrast, the involvement of other endocrine organs in MAS patients was not associated with a particular parent specificity, as precocious puberty and hyperthyroidism were present in patients with mutations on either the maternal or the paternal allele. Moreover, isolated hyperfunctioning thyroid and adrenal adenomas displayed the mutation on the maternal and paternal alleles, respectively. These data confirm the importance of G_s imprinting in the pituitary gland and point out the high degree of tissue specificity of this phenomenon.

This work was supported in part by MURST Grant 2001068427 and Ricerca Corrente Funds from Ospedale Maggiore IRCCS (Milan, Italy).

Abbreviation: MAS, McCune-Albright syndrome.

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