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Entry
- #617686 - PITUITARY ADENOMA 3, MULTIPLE TYPES; PITA3
- OMIM
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<span class="h4">#617686</span>
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<strong>Table of Contents</strong>
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<li role="presentation">
<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/617686"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
<a href="/phenotypicSeries/PS102200"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#clinicalManagement">Clinical Management</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#pathogenesis">Pathogenesis</a>
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<li role="presentation">
<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
<a href="#references"><strong>References</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=(PITUITARY ADENOMA 3, MULTIPLE TYPES) OR (GNAS)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
617686
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<h3>
<span class="mim-font">
PITUITARY ADENOMA 3, MULTIPLE TYPES; PITA3
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
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Gene/Locus <br /> MIM number
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</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/426?start=-3&limit=10&highlight=426">
20q13.32
</a>
</span>
</td>
<td>
<span class="mim-font">
Pituitary adenoma 3, multiple types, somatic
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617686"> 617686 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
GNAS
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/139320"> 139320 </a>
</span>
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<li><a href="/graph/linear/617686" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Somatic mutation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/124975008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">124975008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866227&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866227</a>, <a href="https://bioportal.bioontology.org/search?q=C0544886&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0544886</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001442" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001442</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001442" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001442</a>]</span><br />
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<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
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<div style="margin-left: 2em;">
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<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hyperpigmentation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/4830009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">4830009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/49765009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">49765009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0162834&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162834</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000953" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000953</a>]</span><br />
</span>
</div>
</div>
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</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ENDOCRINE FEATURES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Cushing disease <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/190502001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">190502001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E24.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E24.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221406&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221406</a>]</span><br /> -
Acromegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74107003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74107003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0001206&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001206</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033794" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033794</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033794" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033794</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEOPLASIA </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Pituitary corticotroph adenoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1156936005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1156936005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5548269&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5548269</a>]</span><br /> -
Pituitary somatotroph adenoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1156906001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1156906001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254957009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254957009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0346302&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0346302</a>]</span><br /> -
Mixed pituitary somatotroph-lactotroph adenoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5936364&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5936364</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Elevated serum growth hormone <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5936365&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5936365</a>]</span><br /> -
Elevated serum prolactin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5936366&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5936366</a>]</span><br /> -
Elevated ACTH <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851700&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851700</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by somatic mutation in GNAS complex locus (GNAS, <a href="/entry/139320#0010">139320.0010</a>)<br />
</span>
</div>
</div>
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
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<h5>
Pituitary adenoma
- <a href="/phenotypicSeries/PS102200">PS102200</a>
- 6 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/281?start=-3&limit=10&highlight=281"> 10q22.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617540"> {Pituitary adenoma 5, multiple types} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617540"> 617540 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605516"> CDH23 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605516"> 605516 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/667?start=-3&limit=10&highlight=667"> 11q13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/102200"> Pituitary adenoma predisposition </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/102200"> 102200 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605555"> AIP </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605555"> 605555 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/667?start=-3&limit=10&highlight=667"> 11q13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/102200"> Pituitary adenoma 1, multiple types </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/102200"> 102200 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605555"> AIP </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605555"> 605555 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/206?start=-3&limit=10&highlight=206"> 15q21.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/219090"> Pituitary adenoma 4, ACTH-secreting, somatic </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/219090"> 219090 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603158"> USP8 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603158"> 603158 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/426?start=-3&limit=10&highlight=426"> 20q13.32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617686"> Pituitary adenoma 3, multiple types, somatic </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617686"> 617686 </a>
</span>
</td>
<td>
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<a href="/entry/139320"> GNAS </a>
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<a href="/entry/139320"> 139320 </a>
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<a href="/geneMap/X/727?start=-3&limit=10&highlight=727"> Xq26.3 </a>
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<a href="/entry/300943"> Pituitary adenoma 2, GH-secreting </a>
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<abbr class="mim-tip-hint" title="X-linked">XL</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/300943"> 300943 </a>
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<a href="/entry/300393"> GPR101 </a>
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<a href="/entry/300393"> 300393 </a>
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<p>A number sign (#) is used with this entry because multiple types of pituitary adenomas (PITA3) are caused by somatic mutation in the GNAS gene (<a href="/entry/139320">139320</a>) on chromosome 20q13.</p>
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<p>Somatic mutations in the GNAS gene have been found predominantly in GH-secreting pituitary adenomas but also in ACTH-secreting adenomas.</p><p>Mutations in the GNAS gene have been found in about 40% of sporadic somatotrophin adenomas (summary by <a href="#7" class="mim-tip-reference" title="Mete, O., Lopes, M. B. &lt;strong&gt;Overview of the 2017 WHO classification of pituitary tumors.&lt;/strong&gt; Endocr. Path. 28: 228-243, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28766057/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28766057&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s12022-017-9498-z&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28766057">Mete and Lopes, 2017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28766057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a general description and a discussion of genetic heterogeneity of pituitary adenomas, see PITA1 (<a href="/entry/102200">102200</a>).</p>
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<p><a href="#3" class="mim-tip-reference" title="Barlier, A., Gunz, G., Zamora, A. J., Morange-Ramos, I., Figarella-Branger, D., Dufour, H., Enjalbert, A., Jaquet, P. &lt;strong&gt;Pronostic (sic) and therapeutic consequences of Gs-alpha mutations in somatotroph adenomas.&lt;/strong&gt; J. Clin. Endocr. Metab. 83: 1604-1610, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9589663/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9589663&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.83.5.4797&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9589663">Barlier et al. (1998)</a> found that GNAS-mutant GH-secreting pituitary adenomas secreted significantly more growth hormone relative to tumor size compared to adenomas without GNAS mutations. In vitro and in vivo studies found that the mutant adenomas showed better sensitivity to octreotide; the GH nadir was significantly lower in the mutant adenomas compared to the nonmutant adenomas (85% of maximal inhibition vs 52%). In 18 acromegalic patients treated with octreotide for at least 3 months before surgery, the percent inhibition of GH hypersecretion was higher in those with somatic GNAS-mutant adenomas compared to nonmutant adenomas (76% vs 47%). GH hypersecretion was controlled in all patients with GNAS-mutant adenomas during 2 years of postoperative follow-up, even in those in whom tumor tissue remained after surgery. In contrast, patients with GNAS-negative adenomas did not respond as well to octreotide treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9589663" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Ballare, E., Persani, L., Lania, A. G., Filopanti, M., Giammona, E., Corbetta, S., Mantovani, S., Arosio, M., Beck-Peccoz, P., Faglia, G., Spada, A. &lt;strong&gt;Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 3809-3814, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11502816/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11502816&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.8.7787&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11502816">Ballare et al. (2001)</a> reported a mutation in the SSTR5 gene (<a href="/entry/182455#0001">182455.0001</a>) that abrogated the antiproliferative action of somatostatin and activated mitogenic pathways in a patient with acromegaly resistant to treatment with octreotide who carried an activating GNAS mutation (R201C; <a href="/entry/139320#0008">139320.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11502816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Molecular Genetics</strong>
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<p><a href="#9" class="mim-tip-reference" title="Thakker, R. V., Pook, M. A., Wooding, C., Boscaro, M., Scanarini, M., Clayton, R. N. &lt;strong&gt;Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations.&lt;/strong&gt; J. Clin. Invest. 91: 2815-2821, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8514889/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8514889&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI116524&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8514889">Thakker et al. (1993)</a> found somatic mutations in the GNAS1 gene in 2 non-MEN1 somatotropinomas, one of which also demonstrated allele loss of chromosome 11 (see, e.g., <a href="/entry/139320#0009">139320.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8514889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a series of 32 corticotroph adenomas of the pituitary, <a href="#10" class="mim-tip-reference" title="Williamson, E. A., Ince, P. G., Harrison, D., Kendall-Taylor, P., Harris, P. E. &lt;strong&gt;G-protein mutations in human pituitary adrenocorticotrophic hormone-secreting adenomas.&lt;/strong&gt; Europ. J. Clin. Invest. 25: 128-131, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7737262/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7737262&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1365-2362.1995.tb01537.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7737262">Williamson et al. (1995)</a> found 2 with somatic mutations in the GNAS1 gene at codon 227 (<a href="/entry/139320#0010">139320.0010</a>; <a href="/entry/139320#0012">139320.0012</a>). One of the patients was a 35-year-old male who presented with severe Cushing disease complicated by psychosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7737262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Hayward, B. E., Barlier, A., Korbonits, M., Grossman, A. B., Jacquet, P., Enjalbert, A., Bonthron, D. T. &lt;strong&gt;Imprinting of the G(s)-alpha gene GNAS1 in the pathogenesis of acromegaly.&lt;/strong&gt; J. Clin. Invest. 107: R31-R36, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11254676/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11254676&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11254676[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI11887&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11254676">Hayward et al. (2001)</a> noted that approximately 40% of growth hormone-secreting pituitary adenomas harbor somatic mutations in the GNAS1 gene. Mutations at arg201 or glu227 (see, e.g., <a href="/entry/139320#0008">139320.0008</a> and <a href="/entry/139320#0010">139320.0010</a>, respectively) constitutively activate the alpha subunit of GNAS1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Lania, A., Persani, L., Ballare, E., Mantovani, S., Losa, M., Spada, A. &lt;strong&gt;Constitutively active Gs-alpha is associated with an increased phosphodiesterase activity in human growth hormone-secreting adenomas.&lt;/strong&gt; J. Clin. Endocr. Metab. 83: 1624-1628, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9589667/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9589667&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.83.5.4814&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9589667">Lania et al. (1998)</a> found that 8 GH (<a href="/entry/139250">139250</a>)-secreting adenomas with activating GNAS mutations (gsp+) had similar intracellular cAMP levels as 10 GH-secreting adenomas without GNAS mutations (gsp-). However, pharmacologic inhibition of phosphodiesterase (PDE; see <a href="/entry/171885">171885</a>) induced a marked increase in cAMP in all but 1 mutation-positive adenomas (77 to 2900% increase) and a slight rise in only 2 mutation-negative adenomas. PDE blockade caused a further increase in 3 of 5 mutation-positive adenomas but not in negative tumors. By direct measurement, PDE activity was about 7-fold higher in mutation-positive adenomas. Mutation-positive adenomas also had significantly higher GH release compared to mutation-negative adenomas (315 vs 82 micro g/well; P less than 0.01). <a href="#6" class="mim-tip-reference" title="Lania, A., Persani, L., Ballare, E., Mantovani, S., Losa, M., Spada, A. &lt;strong&gt;Constitutively active Gs-alpha is associated with an increased phosphodiesterase activity in human growth hormone-secreting adenomas.&lt;/strong&gt; J. Clin. Endocr. Metab. 83: 1624-1628, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9589667/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9589667&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.83.5.4814&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9589667">Lania et al. (1998)</a> concluded that activating mutations of the Gs-alpha gene in pituitary adenomas are associated with increased PDE activity that might partially counteract the constitutive activation of the cAMP-dependent pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9589667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Barlier, A., Pellegrini-Bouiller, I., Gunz, G., Zamora, A. J., Jaquet, P., Enjalbert, A. &lt;strong&gt;Impact of gsp oncogene on the expression of genes coding for Gs-alpha, Pit-1, Gi2-alpha, and somatostatin receptor 2 in human somatotroph adenomas: involvement in octreotide sensitivity.&lt;/strong&gt; J. Clin. Endocr. Metab. 84: 2759-2765, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10443675/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10443675&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.84.8.5919&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10443675">Barlier et al. (1999)</a> found that somatotroph adenomas with GNAS mutations (gsp+) had decreased expression of the Gs-alpha gene compared to GNAS-negative (gsp-) tumors, suggesting the existence of a negative feedback of the oncogenic protein upon its own mRNA. In contrast, Gi2-alpha (GNAI2; <a href="/entry/139360">139360</a>), PIT1 (POU1F1; <a href="/entry/173110">173110</a>), and GH mRNAs were not significantly different between the 2 groups. There was a positive correlation between octreotide-induced inhibition of GH secretion and the expression of SSTR2 (<a href="/entry/182452">182452</a>) mRNA, although the expression of the SSTR2 gene did not differ between gsp+ and gsp- adenomas. SSTR2 gene expression was significantly correlated to that of Gi2-alpha and PIT1, and Gs-alpha mRNA expression was positively correlated with that of Gi2-alpha and PIT1. The authors concluded there is a concerted dysregulation of the expression of these genes, which are involved in secretory activity, in both categories of adenomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10443675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Persani, L., Borgato, S., Lania, A., Filopanti, M., Mantovani, G., Conti, M., Spada, A. &lt;strong&gt;Relevant cAMP-specific phosphodiesterase isoforms in human pituitary: effect of Gs-alpha mutations.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 3795-3800, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11502813/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11502813&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.8.7779&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11502813">Persani et al. (2001)</a> found that normal pituitary and gsp- GH-secreting adenomas showed similar PDE activities, whereas gsp+ tumors showed 7-fold higher PDE levels. In gsp+ tumors, the increased activity was mainly due to isobutyl-methyl-xanthine-sensitive phosphodiesterase-4 and to isobutyl-methyl-xanthine-insensitive isoforms. By semiquantitative RT-PCR, all phosphodiesterase-4 transcripts were expressed in the normal and tumoral pituitary. However, the levels of phosphodiesterase-4C (<a href="/entry/600128">600128</a>) and -4D (<a href="/entry/600129">600129</a>) mRNAs were significantly higher in gsp+ than in gsp- GH-secreting adenomas and normal pituitary. Expression of the thyroid-specific isobutyl-methyl-xanthine-insensitive phosphodiesterase-8B (<a href="/entry/603390">603390</a>) was absent in the normal pituitary but detectable in almost all GH-secreting adenomas and higher in gsp+ (P less than 0.02). The authors concluded that up-regulation of PDEs is a mechanism to counteract the constitutive activation of cAMP production and may have a significant impact on the phenotypic expression of gsp mutations such as the rates of GH secretion or tumor growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11502813" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>See Also:</strong>
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<a href="#Ballare1998" class="mim-tip-reference" title="Ballare, E., Mantovani, S., Lania, A., Di Blasio, A. M., Vallar, L., Spada, A. &lt;strong&gt;Activating mutations of the GS-alpha gene are associated with low levels of GS-alpha protein in growth hormone-secreting tumors.&lt;/strong&gt; J. Clin. Endocr. Metab. 83: 4386-4390, 1998.">Ballare et al. (1998)</a>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Ballare1998" class="mim-anchor"></a>
<div class="">
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Ballare, E., Mantovani, S., Lania, A., Di Blasio, A. M., Vallar, L., Spada, A.
<strong>Activating mutations of the GS-alpha gene are associated with low levels of GS-alpha protein in growth hormone-secreting tumors.</strong>
J. Clin. Endocr. Metab. 83: 4386-4390, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9851782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9851782</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9851782" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jcem.83.12.5354" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
<a id="Ballare2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ballare, E., Persani, L., Lania, A. G., Filopanti, M., Giammona, E., Corbetta, S., Mantovani, S., Arosio, M., Beck-Peccoz, P., Faglia, G., Spada, A.
<strong>Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment.</strong>
J. Clin. Endocr. Metab. 86: 3809-3814, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502816</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11502816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jcem.86.8.7787" target="_blank">Full Text</a>]
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<a id="Barlier1998" class="mim-anchor"></a>
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Barlier, A., Gunz, G., Zamora, A. J., Morange-Ramos, I., Figarella-Branger, D., Dufour, H., Enjalbert, A., Jaquet, P.
<strong>Pronostic (sic) and therapeutic consequences of Gs-alpha mutations in somatotroph adenomas.</strong>
J. Clin. Endocr. Metab. 83: 1604-1610, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9589663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9589663</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9589663" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jcem.83.5.4797" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
<a id="Barlier1999" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Barlier, A., Pellegrini-Bouiller, I., Gunz, G., Zamora, A. J., Jaquet, P., Enjalbert, A.
<strong>Impact of gsp oncogene on the expression of genes coding for Gs-alpha, Pit-1, Gi2-alpha, and somatostatin receptor 2 in human somatotroph adenomas: involvement in octreotide sensitivity.</strong>
J. Clin. Endocr. Metab. 84: 2759-2765, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10443675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10443675</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10443675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jcem.84.8.5919" target="_blank">Full Text</a>]
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<a id="Hayward2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hayward, B. E., Barlier, A., Korbonits, M., Grossman, A. B., Jacquet, P., Enjalbert, A., Bonthron, D. T.
<strong>Imprinting of the G(s)-alpha gene GNAS1 in the pathogenesis of acromegaly.</strong>
J. Clin. Invest. 107: R31-R36, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254676</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254676[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI11887" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
<a id="Lania1998" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lania, A., Persani, L., Ballare, E., Mantovani, S., Losa, M., Spada, A.
<strong>Constitutively active Gs-alpha is associated with an increased phosphodiesterase activity in human growth hormone-secreting adenomas.</strong>
J. Clin. Endocr. Metab. 83: 1624-1628, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9589667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9589667</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9589667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jcem.83.5.4814" target="_blank">Full Text</a>]
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<a id="Mete2017" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Mete, O., Lopes, M. B.
<strong>Overview of the 2017 WHO classification of pituitary tumors.</strong>
Endocr. Path. 28: 228-243, 2017.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28766057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28766057</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28766057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s12022-017-9498-z" target="_blank">Full Text</a>]
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<a id="Persani2001" class="mim-anchor"></a>
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<p class="mim-text-font">
Persani, L., Borgato, S., Lania, A., Filopanti, M., Mantovani, G., Conti, M., Spada, A.
<strong>Relevant cAMP-specific phosphodiesterase isoforms in human pituitary: effect of Gs-alpha mutations.</strong>
J. Clin. Endocr. Metab. 86: 3795-3800, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502813</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11502813" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jcem.86.8.7779" target="_blank">Full Text</a>]
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<a id="Thakker1993" class="mim-anchor"></a>
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Thakker, R. V., Pook, M. A., Wooding, C., Boscaro, M., Scanarini, M., Clayton, R. N.
<strong>Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations.</strong>
J. Clin. Invest. 91: 2815-2821, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8514889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8514889</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8514889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI116524" target="_blank">Full Text</a>]
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<a id="Williamson1995" class="mim-anchor"></a>
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Williamson, E. A., Ince, P. G., Harrison, D., Kendall-Taylor, P., Harris, P. E.
<strong>G-protein mutations in human pituitary adrenocorticotrophic hormone-secreting adenomas.</strong>
Europ. J. Clin. Invest. 25: 128-131, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7737262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7737262</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7737262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1365-2362.1995.tb01537.x" target="_blank">Full Text</a>]
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Ada Hamosh : 09/22/2017
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carol : 09/27/2017
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carol : 09/26/2017
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<strong>#</strong> 617686
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<span class="mim-font">
PITUITARY ADENOMA 3, MULTIPLE TYPES; PITA3
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<strong>DO:</strong> 0112010; &nbsp;
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<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<th>
Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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20q13.32
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Pituitary adenoma 3, multiple types, somatic
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617686
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</span>
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3
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GNAS
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<span class="mim-font">
139320
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<strong>TEXT</strong>
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<span class="mim-text-font">
<p>A number sign (#) is used with this entry because multiple types of pituitary adenomas (PITA3) are caused by somatic mutation in the GNAS gene (139320) on chromosome 20q13.</p>
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<strong>Description</strong>
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<p>Somatic mutations in the GNAS gene have been found predominantly in GH-secreting pituitary adenomas but also in ACTH-secreting adenomas.</p><p>Mutations in the GNAS gene have been found in about 40% of sporadic somatotrophin adenomas (summary by Mete and Lopes, 2017). </p><p>For a general description and a discussion of genetic heterogeneity of pituitary adenomas, see PITA1 (102200).</p>
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<strong>Clinical Management</strong>
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<p>Barlier et al. (1998) found that GNAS-mutant GH-secreting pituitary adenomas secreted significantly more growth hormone relative to tumor size compared to adenomas without GNAS mutations. In vitro and in vivo studies found that the mutant adenomas showed better sensitivity to octreotide; the GH nadir was significantly lower in the mutant adenomas compared to the nonmutant adenomas (85% of maximal inhibition vs 52%). In 18 acromegalic patients treated with octreotide for at least 3 months before surgery, the percent inhibition of GH hypersecretion was higher in those with somatic GNAS-mutant adenomas compared to nonmutant adenomas (76% vs 47%). GH hypersecretion was controlled in all patients with GNAS-mutant adenomas during 2 years of postoperative follow-up, even in those in whom tumor tissue remained after surgery. In contrast, patients with GNAS-negative adenomas did not respond as well to octreotide treatment. </p><p>Ballare et al. (2001) reported a mutation in the SSTR5 gene (182455.0001) that abrogated the antiproliferative action of somatostatin and activated mitogenic pathways in a patient with acromegaly resistant to treatment with octreotide who carried an activating GNAS mutation (R201C; 139320.0008). </p>
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<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
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<p>Thakker et al. (1993) found somatic mutations in the GNAS1 gene in 2 non-MEN1 somatotropinomas, one of which also demonstrated allele loss of chromosome 11 (see, e.g., 139320.0009). </p><p>In a series of 32 corticotroph adenomas of the pituitary, Williamson et al. (1995) found 2 with somatic mutations in the GNAS1 gene at codon 227 (139320.0010; 139320.0012). One of the patients was a 35-year-old male who presented with severe Cushing disease complicated by psychosis. </p><p>Hayward et al. (2001) noted that approximately 40% of growth hormone-secreting pituitary adenomas harbor somatic mutations in the GNAS1 gene. Mutations at arg201 or glu227 (see, e.g., 139320.0008 and 139320.0010, respectively) constitutively activate the alpha subunit of GNAS1. </p>
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<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Lania et al. (1998) found that 8 GH (139250)-secreting adenomas with activating GNAS mutations (gsp+) had similar intracellular cAMP levels as 10 GH-secreting adenomas without GNAS mutations (gsp-). However, pharmacologic inhibition of phosphodiesterase (PDE; see 171885) induced a marked increase in cAMP in all but 1 mutation-positive adenomas (77 to 2900% increase) and a slight rise in only 2 mutation-negative adenomas. PDE blockade caused a further increase in 3 of 5 mutation-positive adenomas but not in negative tumors. By direct measurement, PDE activity was about 7-fold higher in mutation-positive adenomas. Mutation-positive adenomas also had significantly higher GH release compared to mutation-negative adenomas (315 vs 82 micro g/well; P less than 0.01). Lania et al. (1998) concluded that activating mutations of the Gs-alpha gene in pituitary adenomas are associated with increased PDE activity that might partially counteract the constitutive activation of the cAMP-dependent pathway. </p><p>Barlier et al. (1999) found that somatotroph adenomas with GNAS mutations (gsp+) had decreased expression of the Gs-alpha gene compared to GNAS-negative (gsp-) tumors, suggesting the existence of a negative feedback of the oncogenic protein upon its own mRNA. In contrast, Gi2-alpha (GNAI2; 139360), PIT1 (POU1F1; 173110), and GH mRNAs were not significantly different between the 2 groups. There was a positive correlation between octreotide-induced inhibition of GH secretion and the expression of SSTR2 (182452) mRNA, although the expression of the SSTR2 gene did not differ between gsp+ and gsp- adenomas. SSTR2 gene expression was significantly correlated to that of Gi2-alpha and PIT1, and Gs-alpha mRNA expression was positively correlated with that of Gi2-alpha and PIT1. The authors concluded there is a concerted dysregulation of the expression of these genes, which are involved in secretory activity, in both categories of adenomas. </p><p>Persani et al. (2001) found that normal pituitary and gsp- GH-secreting adenomas showed similar PDE activities, whereas gsp+ tumors showed 7-fold higher PDE levels. In gsp+ tumors, the increased activity was mainly due to isobutyl-methyl-xanthine-sensitive phosphodiesterase-4 and to isobutyl-methyl-xanthine-insensitive isoforms. By semiquantitative RT-PCR, all phosphodiesterase-4 transcripts were expressed in the normal and tumoral pituitary. However, the levels of phosphodiesterase-4C (600128) and -4D (600129) mRNAs were significantly higher in gsp+ than in gsp- GH-secreting adenomas and normal pituitary. Expression of the thyroid-specific isobutyl-methyl-xanthine-insensitive phosphodiesterase-8B (603390) was absent in the normal pituitary but detectable in almost all GH-secreting adenomas and higher in gsp+ (P less than 0.02). The authors concluded that up-regulation of PDEs is a mechanism to counteract the constitutive activation of cAMP production and may have a significant impact on the phenotypic expression of gsp mutations such as the rates of GH secretion or tumor growth. </p>
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<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Ballare et al. (1998)
</span>
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</div>
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<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Ballare, E., Mantovani, S., Lania, A., Di Blasio, A. M., Vallar, L., Spada, A.
<strong>Activating mutations of the GS-alpha gene are associated with low levels of GS-alpha protein in growth hormone-secreting tumors.</strong>
J. Clin. Endocr. Metab. 83: 4386-4390, 1998.
[PubMed: 9851782]
[Full Text: https://doi.org/10.1210/jcem.83.12.5354]
</p>
</li>
<li>
<p class="mim-text-font">
Ballare, E., Persani, L., Lania, A. G., Filopanti, M., Giammona, E., Corbetta, S., Mantovani, S., Arosio, M., Beck-Peccoz, P., Faglia, G., Spada, A.
<strong>Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment.</strong>
J. Clin. Endocr. Metab. 86: 3809-3814, 2001.
[PubMed: 11502816]
[Full Text: https://doi.org/10.1210/jcem.86.8.7787]
</p>
</li>
<li>
<p class="mim-text-font">
Barlier, A., Gunz, G., Zamora, A. J., Morange-Ramos, I., Figarella-Branger, D., Dufour, H., Enjalbert, A., Jaquet, P.
<strong>Pronostic (sic) and therapeutic consequences of Gs-alpha mutations in somatotroph adenomas.</strong>
J. Clin. Endocr. Metab. 83: 1604-1610, 1998.
[PubMed: 9589663]
[Full Text: https://doi.org/10.1210/jcem.83.5.4797]
</p>
</li>
<li>
<p class="mim-text-font">
Barlier, A., Pellegrini-Bouiller, I., Gunz, G., Zamora, A. J., Jaquet, P., Enjalbert, A.
<strong>Impact of gsp oncogene on the expression of genes coding for Gs-alpha, Pit-1, Gi2-alpha, and somatostatin receptor 2 in human somatotroph adenomas: involvement in octreotide sensitivity.</strong>
J. Clin. Endocr. Metab. 84: 2759-2765, 1999.
[PubMed: 10443675]
[Full Text: https://doi.org/10.1210/jcem.84.8.5919]
</p>
</li>
<li>
<p class="mim-text-font">
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<strong>Imprinting of the G(s)-alpha gene GNAS1 in the pathogenesis of acromegaly.</strong>
J. Clin. Invest. 107: R31-R36, 2001.
[PubMed: 11254676]
[Full Text: https://doi.org/10.1172/JCI11887]
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Lania, A., Persani, L., Ballare, E., Mantovani, S., Losa, M., Spada, A.
<strong>Constitutively active Gs-alpha is associated with an increased phosphodiesterase activity in human growth hormone-secreting adenomas.</strong>
J. Clin. Endocr. Metab. 83: 1624-1628, 1998.
[PubMed: 9589667]
[Full Text: https://doi.org/10.1210/jcem.83.5.4814]
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Mete, O., Lopes, M. B.
<strong>Overview of the 2017 WHO classification of pituitary tumors.</strong>
Endocr. Path. 28: 228-243, 2017.
[PubMed: 28766057]
[Full Text: https://doi.org/10.1007/s12022-017-9498-z]
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Persani, L., Borgato, S., Lania, A., Filopanti, M., Mantovani, G., Conti, M., Spada, A.
<strong>Relevant cAMP-specific phosphodiesterase isoforms in human pituitary: effect of Gs-alpha mutations.</strong>
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Williamson, E. A., Ince, P. G., Harrison, D., Kendall-Taylor, P., Harris, P. E.
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