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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.
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Abstract |
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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 Gs gene is subjected to imprinting control and that Gs 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 Gs 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 Gs 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, Gs 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 Gs imprinting in the pituitary gland and point out the high degree of tissue specificity of this phenomenon. |
Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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gene (the so-called gsp oncogene) (1, 2) are known to be involved in the pathogenesis of different human endocrine diseases, such as sporadic endocrine tumors, in particular GH-secreting pituitary adenomas and autonomous thyroid adenomas, and the McCune-Albright syndrome (MAS). MAS is a sporadic disorder characterized by polyostotic fibrous dysplasia, café-au-lait skin hyperpigmentation, and autonomous hyperfunction of several endocrine glands, such as gonads, pituitary, thyroid, and adrenal cortex, i.e. glands sensitive to trophic agents acting through the cAMP-dependent pathway (3, 4). Mutations of the Gs gene have been detected in all affected subjects, and Arg201 is the only location reported in MAS to date. Mutant Gs is expressed in the affected endocrine organs as well as in tissues not classically involved in MAS; the highest proportion of mutant alleles is found in regions of abnormal proliferation. This mosaic distribution is consistent with the hypothesis that this syndrome is due to a somatic mutation in the Gs gene occurring as an early postzygotic event.
The human Gs gene maps on chromosome 20q13, and there is increasing evidence that this locus is under complex imprinting control with multiple maternally, paternally, and biallelically alternatively spliced transcripts encoding multiple products (5, 6, 7, 8, 9). Recent reports demonstrated that in thyroid, gonad, and pituitary, Gs transcription mainly derives from the maternal allele (10, 11, 12, 13). Moreover, it has been demonstrated that in most gsp-positive GH-secreting pituitary tumors the mutation occurs on the maternal allele (10), most likely indicating that the same mutations on the paternal allele are clinically silent.
The aim of this study was to determine the parental allele that harbors Arg201 or Gln227 mutations in affected tissues from patients with the McCune-Albright syndrome and in isolated hyperfunctioning endocrine tumors.
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Patients and Methods |
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The study included 10 patients affected with MAS, some of whom have already been described in a previous report (14). In all patients (six females and four males, aged 6–52 yr) the diagnosis was based upon the occurrence of classical MAS features, such as polyostotic fibrous dysplasia, café-au-lait skin hyperpigmentation, and autonomous endocrine hyperfunction. Some clinical features of these patients are shown in Table 1
. Moreover, we collected 10 GH-secreting pituitary tumors, one toxic thyroid adenoma, and one cortisol-secreting adrenal tumor, all of which have been previously been characterized and defined gsp+ (15, 16). Informed consent was obtained from all subjects involved in the study. The study was approved by the local ethical committee.
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After obtaining written consent, DNA and RNA were extracted from the affected tissues (Table 2) using standard procedures (11, 17) . The Gs gene (GenBank accession no.AH002748) was then amplified by PCR using the specific primers amplifying exons 8 and 9, where Arg201 and Gln227 are located, as previously described (15, 16). Direct sequencing of the amplified fragments was then performed using the AmpliTaq BigDye Terminator kit and 310 Genetic Analyzer (PerkinElmer Applied Biosystems, Foster City, CA).
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(GenBank accession no. M21139 J03647, nucleotides 789–807), exon 1A (GenBank accession no. AF 246983, nucleotides 1692–1711), and NESP55 (GenBank accession no. AJ 251760, nucleotides 1432–1451) genes, respectively (Gs, 5'-CCATGGGCTGCCTCGGGAACA-3'; exon 1A, 5'-CCTTGCGTGTGAGTGCACCT-3'; NESP55, 5'-AGCCCGAGGACAAAGATCCA-3') (11). The amplified fragments were then subjected to direct sequencing using the common downstream primer located in exon 10. |
Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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gene in all samples from MAS patients and mutations at either codon 201 or 227 in samples from the other hyperfunctioning adenomas (see Table 2
for details). Analysis of the mutated codon from the RNA of MAS samples showed that the mutation was present on either the maternal or the paternal allele (Table 2). In particular, the mutation, but not wild-type, sequence was detected in the NESP55 transcripts (which exclusively derive from the maternal allele) in six patients and in exon 1A transcripts (which derive from the paternal allele) in four. Interestingly, the two MAS patients with acromegaly had mutations on the maternal allele, whereas no correlation between the allele bearing the mutation and the other clinical manifestations of MAS was observed (Table 1). In particular, of the five MAS patients with precocious puberty, one had the mutation on the maternal allele (patient 2) and four had the mutation on the paternal one (patients 4, 5, 7, and 8), whereas of the two hyperthyroid patients, the mutation was on the maternal allele in patient 6 and on the paternal allele in patient 5. Among the isolated hyperfunctioning adenomas, all GH-secreting adenomas had the mutation on the maternal allele, the toxic thyroid adenoma on the maternal allele, and the hyperfunctioning adrenal adenoma on the paternal allele. A schematic representation of the distribution of the parental alleles that harbored gsp mutations in the different tumors considered in this study is given in Table 3, whereas Fig. 1 shows an example of Gs, exon 1A, and NESP55 sequences from the same sample.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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mutations in patients with MAS and in isolated hyperfunctioning endocrine tumors. The parental allele harboring Gs mutations was assessed by evaluating NESP55 and exon 1A transcripts, which have been shown to be monoallelically expressed from the maternal and paternal alleles, respectively (6, 7, 8). By this approach, we demonstrated that the Gs mutation occurred exclusively on the maternal allele in GH-secreting adenomas, whereas both maternal and paternal alleles could be affected in the other tumors. The finding of a specific maternal origin of the gsp oncogene in pituitary adenomas confirms a previous report from Hayward and colleagues (10) and is in agreement with the demonstration of an almost exclusive maternal origin of Gs transcription in the human normal pituitary (10, 11). It is therefore likely that in this gland the same mutation occurring on the paternal allele would be clinically silent.
On the contrary, our observation of the presence of gsp mutations on the paternal allele in affected tissues from patients with MAS is consistent with the idea that the imprinting of Gs is a tissue-specific phenomenon. In particular, the presence of precocious puberty and hyperthyroidism in MAS patients independently from the parental allele harboring the mutation is in agreement with the predominant, but not exclusive, maternal expression of this gene in thyroid and gonads (11, 12, 13). It is therefore conceivable that paternal mutations in tissues with variable, but not negligible, paternal contribution to Gs expression (
20–30% in our laboratory) (11) would still be able to have clinical significance. It is of interest that the two patients with MAS and GH-secreting adenomas displayed the mutation on the maternal allele, whereas none of the patients affected with MAS with the Gs mutation on the paternal allele had any sign of GH hypersecretion at the time of this study. It is therefore tempting to speculate that, given the nearly absent expression of the Gs gene from the paternal allele in the pituitary (10, 11), only mutations on the maternal allele are able to give raise to GH-secreting adenomas in these patients, as seems to happen in isolated acromegaly. However, it must be noted that these observations derive from a relatively small number of cases and that young patients could display other endocrine dysfunctions in the future.
In contrast to acromegaly, which seems to appear only in patients with a mutation on the maternal allele, bone and skin were invariably affected in all patients with MAS. It is worth pointing out that despite the fact that four of the five bone specimens analyzed developed in the setting of a maternally derived gsp, all of the patients included in this study presented with both bone and skin lesions, thus excluding a specific maternal origin of the mutation in osteodysplasia. This observation suggests the absence of Gs imprinting in such tissues and is consistent with the evidence of osteodystrophy in subjects affected with pseudopseudohypoparathyroidism, a disease associated with loss of function mutations of the Gs gene on the paternal allele.
As for isolated autonomous thyroid adenomas and adrenal tumors, in our opinion no speculation is possible at this time given the small number of cases included in our study. This limitation will not be easily overcome due to the extreme rarity of the gsp oncogene in these tumors.
In conclusion, our study confirms previous work demonstrating the presence of the gsp oncogene exclusively on the maternal allele in isolated GH-secreting pituitary adenomas. Moreover, it further extends the role played by Gs imprinting in human disease, correlating the presence of acromegaly in the MAS only in those patients carrying the activating mutation on the maternal allele.
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Footnotes |
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Abbreviation: MAS, McCune-Albright syndrome.
Received February 5, 2004.
Accepted March 18, 2004.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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chain of Gs and stimulate adenylyl cyclase in human pituitary tumors. Nature 340:692–696[CrossRef][Medline]
. J Biol Biochem 264:15475–15482
subunit of the stimulatory G-protein of adenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci USA 89:5152–5156-subunit (Gs) knockout mice is due to tissue-specific imprinting of the Gs gene. Proc Natl Acad Sci USA 95:8715–8720s gene GNAS1 in the pathogenesis of acromegaly. J Clin Invest 107:R31–R36
gene: predominant maternal origin of transcription in human thyroid gland and gonads. J Clin Endocrinol Metab 87:4736–4740s in the human thyroid as the basis of TSH resistance in pseudohypoparathyroidism type 1a. Biochem Biophys Res Commun 296:67–72[CrossRef][Medline]
-subunit Gs is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. J Clin Endocrinol Metab 8:4336–4341
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