ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences
Context: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of primary adrenal Cushing's syndrome (CS). ARMC5 germline mutations have been identified recently in PBMAH. Objective: To determine the prevalence of ARMC5 mutations and analyze genotype-phenotype correlation i...
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| Veröffentlicht in: | The journal of clinical endocrinology and metabolism 2015-06, Vol.100 (6), p.E926-E935 |
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| creator | Espiard, Stéphanie Drougat, Ludivine Libé, Rossella Assié, Guillaume Perlemoine, Karine Guignat, Laurence Barrande, Gaelle Brucker-Davis, Françoise Doullay, Françoise Lopez, Stephanie Sonnet, Emmanuel Torremocha, Florence Pinsard, Denis Chabbert-Buffet, Nathalie Raffin-Sanson, Marie-Laure Groussin, Lionel Borson-Chazot, Françoise Coste, Joël Bertagna, Xavier Stratakis, Constantine A Beuschlein, Felix Ragazzon, Bruno Bertherat, Jérôme |
| description | Context:
Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of primary adrenal Cushing's syndrome (CS). ARMC5 germline mutations have been identified recently in PBMAH.
Objective:
To determine the prevalence of ARMC5 mutations and analyze genotype-phenotype correlation in a large cohort of unrelated PBMAH patients with subclinical or clinical CS.
Patients and Methods:
ARMC5 was sequenced in 98 unrelated PBMAH index cases. PBMAH was identified by bilateral adrenal nodular enlargement on computed tomography scan. The effect on apoptosis of ARMC5 missense mutants was tested in H295R and HeLa cells. Clinical and hormonal data were collected including midnight and urinary free cortisol levels, ACTH, androgens, renin/aldosterone ratio, cortisol after overnight dexamethasone suppression test, cortisol and 17-hydroxyprogesterone after ACTH 1-24 stimulation and illegitimate receptor responses. Computed tomography and histological reports were analyzed.
Results:
ARMC5-damaging mutations were identified in 24 patients (26%). The missense mutants and the p.F700del deletion were unable to induce apoptosis in both H295R and HeLa cell lines, unlike the wild-type gene. ARMC5-mutated patients showed an overt CS more frequently, compared to wild-type patients: lower ACTH, higher midnight plasma cortisol, urinary free cortisol, and cortisol after dexamethasone suppression test (P = .003, .019, .006, and |
| doi_str_mv | 10.1210/jc.2014-4204 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5393514</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1686414607</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4690-2f496a88a588b06ea8e6d24ebebc316524634663ad56255dbb11e79ab9c7d84e3</originalsourceid><addsrcrecordid>eNptkd-L1DAQx4so3nr65rPkUcGeSfOjiQ_CUjxX2EURBd9Cms7eds0mNWnvuP_elJ6HioEQZvKZ72TyLYrnBF-QiuA3R3tRYcJKVmH2oFgRxXhZE1U_LFYYV6RUdfX9rHiS0hFnjHH6uDiruOS0VnRVpPWXXcPRbhrN2AefUO-RQVsTrwA14RDiiMIefY79ycRbtDM2Bh-6yZmI1l0Ebxza3A4QB2dSb96ixvW-tzlrfIcuJ29n1Rw2WRt-TuAtpKfFo71xCZ7dnefFt8v3X5tNuf304WOz3paWCYXLas-UMFIaLmWLBRgJoqsYtNBaSgSvmKBMCGo6LirOu7YlBGplWmXrTjKg58W7RXeY2hN0FvwYjdPDMowOptd_3_j-oK_CteZUUU5YFni1CBz-Kdust3rOYSIJVUpek8y-vGsWQ54zjfrUJwvOGQ9hSpoIKRhhAtcZfb2g-TNTirC_1yZYz57qo9Wzp3r2NOMv_hzjHv5tYgbYAtwEN0JMP9x0A1EfwLjxoHFeTNSyzIocixyVeQucy-hSBr4LNvYehggp6WOYYrYs_f81vwDTR73Q</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1686414607</pqid></control><display><type>article</type><title>ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences</title><source>MEDLINE</source><source>Journals@Ovid Complete</source><source>Oxford University Press Journals All Titles (1996-Current)</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Espiard, Stéphanie ; Drougat, Ludivine ; Libé, Rossella ; Assié, Guillaume ; Perlemoine, Karine ; Guignat, Laurence ; Barrande, Gaelle ; Brucker-Davis, Françoise ; Doullay, Françoise ; Lopez, Stephanie ; Sonnet, Emmanuel ; Torremocha, Florence ; Pinsard, Denis ; Chabbert-Buffet, Nathalie ; Raffin-Sanson, Marie-Laure ; Groussin, Lionel ; Borson-Chazot, Françoise ; Coste, Joël ; Bertagna, Xavier ; Stratakis, Constantine A ; Beuschlein, Felix ; Ragazzon, Bruno ; Bertherat, Jérôme</creator><creatorcontrib>Espiard, Stéphanie ; Drougat, Ludivine ; Libé, Rossella ; Assié, Guillaume ; Perlemoine, Karine ; Guignat, Laurence ; Barrande, Gaelle ; Brucker-Davis, Françoise ; Doullay, Françoise ; Lopez, Stephanie ; Sonnet, Emmanuel ; Torremocha, Florence ; Pinsard, Denis ; Chabbert-Buffet, Nathalie ; Raffin-Sanson, Marie-Laure ; Groussin, Lionel ; Borson-Chazot, Françoise ; Coste, Joël ; Bertagna, Xavier ; Stratakis, Constantine A ; Beuschlein, Felix ; Ragazzon, Bruno ; Bertherat, Jérôme</creatorcontrib><description>Context:
Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of primary adrenal Cushing's syndrome (CS). ARMC5 germline mutations have been identified recently in PBMAH.
Objective:
To determine the prevalence of ARMC5 mutations and analyze genotype-phenotype correlation in a large cohort of unrelated PBMAH patients with subclinical or clinical CS.
Patients and Methods:
ARMC5 was sequenced in 98 unrelated PBMAH index cases. PBMAH was identified by bilateral adrenal nodular enlargement on computed tomography scan. The effect on apoptosis of ARMC5 missense mutants was tested in H295R and HeLa cells. Clinical and hormonal data were collected including midnight and urinary free cortisol levels, ACTH, androgens, renin/aldosterone ratio, cortisol after overnight dexamethasone suppression test, cortisol and 17-hydroxyprogesterone after ACTH 1-24 stimulation and illegitimate receptor responses. Computed tomography and histological reports were analyzed.
Results:
ARMC5-damaging mutations were identified in 24 patients (26%). The missense mutants and the p.F700del deletion were unable to induce apoptosis in both H295R and HeLa cell lines, unlike the wild-type gene. ARMC5-mutated patients showed an overt CS more frequently, compared to wild-type patients: lower ACTH, higher midnight plasma cortisol, urinary free cortisol, and cortisol after dexamethasone suppression test (P = .003, .019, .006, and <.001, respectively). Adrenals of patients with mutations were bigger and had a higher number of nodules (P = .001 and <.001, respectively).
Conclusions:
ARMC5 germline mutations are common in PBMAH. Index cases of mutation carriers show a more severe hypercortisolism and larger adrenals. ARMC5 genotyping may help to identify clinical forms of PBMAH better and may also allow earlier diagnosis of this disease.</description><identifier>ISSN: 0021-972X</identifier><identifier>EISSN: 1945-7197</identifier><identifier>DOI: 10.1210/jc.2014-4204</identifier><identifier>PMID: 25853793</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>Adrenal Cortex Diseases ; Adrenal Cortex Diseases - epidemiology ; Adrenal Cortex Diseases - genetics ; Adrenal Glands ; Adrenal Glands - pathology ; Adult ; Aged ; Cells, Cultured ; Cohort Studies ; Cushing Syndrome ; Cushing Syndrome - epidemiology ; Cushing Syndrome - genetics ; DNA Mutational Analysis ; Female ; Genetic Association Studies ; HeLa Cells ; Humans ; Hyperplasia ; Hyperplasia - genetics ; Hyperplasia - pathology ; JCEM Online: Advances in Genetics ; Life Sciences ; Male ; Middle Aged ; Mutation, Missense ; Santé publique et épidémiologie ; Tumor Suppressor Proteins ; Tumor Suppressor Proteins - genetics</subject><ispartof>The journal of clinical endocrinology and metabolism, 2015-06, Vol.100 (6), p.E926-E935</ispartof><rights>Copyright © 2015 by the Endocrine Society</rights><rights>Copyright © 2015 by The Endocrine Society</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>Copyright © 2015 by the Endocrine Society 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4690-2f496a88a588b06ea8e6d24ebebc316524634663ad56255dbb11e79ab9c7d84e3</citedby><orcidid>0000-0001-7826-3984 ; 0000-0001-9476-4973 ; 0000-0001-9590-0906 ; 0000-0003-2515-7840</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25853793$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.univ-lorraine.fr/hal-01813998$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Espiard, Stéphanie</creatorcontrib><creatorcontrib>Drougat, Ludivine</creatorcontrib><creatorcontrib>Libé, Rossella</creatorcontrib><creatorcontrib>Assié, Guillaume</creatorcontrib><creatorcontrib>Perlemoine, Karine</creatorcontrib><creatorcontrib>Guignat, Laurence</creatorcontrib><creatorcontrib>Barrande, Gaelle</creatorcontrib><creatorcontrib>Brucker-Davis, Françoise</creatorcontrib><creatorcontrib>Doullay, Françoise</creatorcontrib><creatorcontrib>Lopez, Stephanie</creatorcontrib><creatorcontrib>Sonnet, Emmanuel</creatorcontrib><creatorcontrib>Torremocha, Florence</creatorcontrib><creatorcontrib>Pinsard, Denis</creatorcontrib><creatorcontrib>Chabbert-Buffet, Nathalie</creatorcontrib><creatorcontrib>Raffin-Sanson, Marie-Laure</creatorcontrib><creatorcontrib>Groussin, Lionel</creatorcontrib><creatorcontrib>Borson-Chazot, Françoise</creatorcontrib><creatorcontrib>Coste, Joël</creatorcontrib><creatorcontrib>Bertagna, Xavier</creatorcontrib><creatorcontrib>Stratakis, Constantine A</creatorcontrib><creatorcontrib>Beuschlein, Felix</creatorcontrib><creatorcontrib>Ragazzon, Bruno</creatorcontrib><creatorcontrib>Bertherat, Jérôme</creatorcontrib><title>ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences</title><title>The journal of clinical endocrinology and metabolism</title><addtitle>J Clin Endocrinol Metab</addtitle><description>Context:
Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of primary adrenal Cushing's syndrome (CS). ARMC5 germline mutations have been identified recently in PBMAH.
Objective:
To determine the prevalence of ARMC5 mutations and analyze genotype-phenotype correlation in a large cohort of unrelated PBMAH patients with subclinical or clinical CS.
Patients and Methods:
ARMC5 was sequenced in 98 unrelated PBMAH index cases. PBMAH was identified by bilateral adrenal nodular enlargement on computed tomography scan. The effect on apoptosis of ARMC5 missense mutants was tested in H295R and HeLa cells. Clinical and hormonal data were collected including midnight and urinary free cortisol levels, ACTH, androgens, renin/aldosterone ratio, cortisol after overnight dexamethasone suppression test, cortisol and 17-hydroxyprogesterone after ACTH 1-24 stimulation and illegitimate receptor responses. Computed tomography and histological reports were analyzed.
Results:
ARMC5-damaging mutations were identified in 24 patients (26%). The missense mutants and the p.F700del deletion were unable to induce apoptosis in both H295R and HeLa cell lines, unlike the wild-type gene. ARMC5-mutated patients showed an overt CS more frequently, compared to wild-type patients: lower ACTH, higher midnight plasma cortisol, urinary free cortisol, and cortisol after dexamethasone suppression test (P = .003, .019, .006, and <.001, respectively). Adrenals of patients with mutations were bigger and had a higher number of nodules (P = .001 and <.001, respectively).
Conclusions:
ARMC5 germline mutations are common in PBMAH. Index cases of mutation carriers show a more severe hypercortisolism and larger adrenals. ARMC5 genotyping may help to identify clinical forms of PBMAH better and may also allow earlier diagnosis of this disease.</description><subject>Adrenal Cortex Diseases</subject><subject>Adrenal Cortex Diseases - epidemiology</subject><subject>Adrenal Cortex Diseases - genetics</subject><subject>Adrenal Glands</subject><subject>Adrenal Glands - pathology</subject><subject>Adult</subject><subject>Aged</subject><subject>Cells, Cultured</subject><subject>Cohort Studies</subject><subject>Cushing Syndrome</subject><subject>Cushing Syndrome - epidemiology</subject><subject>Cushing Syndrome - genetics</subject><subject>DNA Mutational Analysis</subject><subject>Female</subject><subject>Genetic Association Studies</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Hyperplasia</subject><subject>Hyperplasia - genetics</subject><subject>Hyperplasia - pathology</subject><subject>JCEM Online: Advances in Genetics</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mutation, Missense</subject><subject>Santé publique et épidémiologie</subject><subject>Tumor Suppressor Proteins</subject><subject>Tumor Suppressor Proteins - genetics</subject><issn>0021-972X</issn><issn>1945-7197</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkd-L1DAQx4so3nr65rPkUcGeSfOjiQ_CUjxX2EURBd9Cms7eds0mNWnvuP_elJ6HioEQZvKZ72TyLYrnBF-QiuA3R3tRYcJKVmH2oFgRxXhZE1U_LFYYV6RUdfX9rHiS0hFnjHH6uDiruOS0VnRVpPWXXcPRbhrN2AefUO-RQVsTrwA14RDiiMIefY79ycRbtDM2Bh-6yZmI1l0Ebxza3A4QB2dSb96ixvW-tzlrfIcuJ29n1Rw2WRt-TuAtpKfFo71xCZ7dnefFt8v3X5tNuf304WOz3paWCYXLas-UMFIaLmWLBRgJoqsYtNBaSgSvmKBMCGo6LirOu7YlBGplWmXrTjKg58W7RXeY2hN0FvwYjdPDMowOptd_3_j-oK_CteZUUU5YFni1CBz-Kdust3rOYSIJVUpek8y-vGsWQ54zjfrUJwvOGQ9hSpoIKRhhAtcZfb2g-TNTirC_1yZYz57qo9Wzp3r2NOMv_hzjHv5tYgbYAtwEN0JMP9x0A1EfwLjxoHFeTNSyzIocixyVeQucy-hSBr4LNvYehggp6WOYYrYs_f81vwDTR73Q</recordid><startdate>201506</startdate><enddate>201506</enddate><creator>Espiard, Stéphanie</creator><creator>Drougat, Ludivine</creator><creator>Libé, Rossella</creator><creator>Assié, Guillaume</creator><creator>Perlemoine, Karine</creator><creator>Guignat, Laurence</creator><creator>Barrande, Gaelle</creator><creator>Brucker-Davis, Françoise</creator><creator>Doullay, Françoise</creator><creator>Lopez, Stephanie</creator><creator>Sonnet, Emmanuel</creator><creator>Torremocha, Florence</creator><creator>Pinsard, Denis</creator><creator>Chabbert-Buffet, Nathalie</creator><creator>Raffin-Sanson, Marie-Laure</creator><creator>Groussin, Lionel</creator><creator>Borson-Chazot, Françoise</creator><creator>Coste, Joël</creator><creator>Bertagna, Xavier</creator><creator>Stratakis, Constantine A</creator><creator>Beuschlein, Felix</creator><creator>Ragazzon, Bruno</creator><creator>Bertherat, Jérôme</creator><general>Endocrine Society</general><general>Copyright by The Endocrine Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>1XC</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7826-3984</orcidid><orcidid>https://orcid.org/0000-0001-9476-4973</orcidid><orcidid>https://orcid.org/0000-0001-9590-0906</orcidid><orcidid>https://orcid.org/0000-0003-2515-7840</orcidid></search><sort><creationdate>201506</creationdate><title>ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences</title><author>Espiard, Stéphanie ; Drougat, Ludivine ; Libé, Rossella ; Assié, Guillaume ; Perlemoine, Karine ; Guignat, Laurence ; Barrande, Gaelle ; Brucker-Davis, Françoise ; Doullay, Françoise ; Lopez, Stephanie ; Sonnet, Emmanuel ; Torremocha, Florence ; Pinsard, Denis ; Chabbert-Buffet, Nathalie ; Raffin-Sanson, Marie-Laure ; Groussin, Lionel ; Borson-Chazot, Françoise ; Coste, Joël ; Bertagna, Xavier ; Stratakis, Constantine A ; Beuschlein, Felix ; Ragazzon, Bruno ; Bertherat, Jérôme</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4690-2f496a88a588b06ea8e6d24ebebc316524634663ad56255dbb11e79ab9c7d84e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adrenal Cortex Diseases</topic><topic>Adrenal Cortex Diseases - epidemiology</topic><topic>Adrenal Cortex Diseases - genetics</topic><topic>Adrenal Glands</topic><topic>Adrenal Glands - pathology</topic><topic>Adult</topic><topic>Aged</topic><topic>Cells, Cultured</topic><topic>Cohort Studies</topic><topic>Cushing Syndrome</topic><topic>Cushing Syndrome - epidemiology</topic><topic>Cushing Syndrome - genetics</topic><topic>DNA Mutational Analysis</topic><topic>Female</topic><topic>Genetic Association Studies</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Hyperplasia</topic><topic>Hyperplasia - genetics</topic><topic>Hyperplasia - pathology</topic><topic>JCEM Online: Advances in Genetics</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mutation, Missense</topic><topic>Santé publique et épidémiologie</topic><topic>Tumor Suppressor Proteins</topic><topic>Tumor Suppressor Proteins - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Espiard, Stéphanie</creatorcontrib><creatorcontrib>Drougat, Ludivine</creatorcontrib><creatorcontrib>Libé, Rossella</creatorcontrib><creatorcontrib>Assié, Guillaume</creatorcontrib><creatorcontrib>Perlemoine, Karine</creatorcontrib><creatorcontrib>Guignat, Laurence</creatorcontrib><creatorcontrib>Barrande, Gaelle</creatorcontrib><creatorcontrib>Brucker-Davis, Françoise</creatorcontrib><creatorcontrib>Doullay, Françoise</creatorcontrib><creatorcontrib>Lopez, Stephanie</creatorcontrib><creatorcontrib>Sonnet, Emmanuel</creatorcontrib><creatorcontrib>Torremocha, Florence</creatorcontrib><creatorcontrib>Pinsard, Denis</creatorcontrib><creatorcontrib>Chabbert-Buffet, Nathalie</creatorcontrib><creatorcontrib>Raffin-Sanson, Marie-Laure</creatorcontrib><creatorcontrib>Groussin, Lionel</creatorcontrib><creatorcontrib>Borson-Chazot, Françoise</creatorcontrib><creatorcontrib>Coste, Joël</creatorcontrib><creatorcontrib>Bertagna, Xavier</creatorcontrib><creatorcontrib>Stratakis, Constantine A</creatorcontrib><creatorcontrib>Beuschlein, Felix</creatorcontrib><creatorcontrib>Ragazzon, Bruno</creatorcontrib><creatorcontrib>Bertherat, Jérôme</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The journal of clinical endocrinology and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Espiard, Stéphanie</au><au>Drougat, Ludivine</au><au>Libé, Rossella</au><au>Assié, Guillaume</au><au>Perlemoine, Karine</au><au>Guignat, Laurence</au><au>Barrande, Gaelle</au><au>Brucker-Davis, Françoise</au><au>Doullay, Françoise</au><au>Lopez, Stephanie</au><au>Sonnet, Emmanuel</au><au>Torremocha, Florence</au><au>Pinsard, Denis</au><au>Chabbert-Buffet, Nathalie</au><au>Raffin-Sanson, Marie-Laure</au><au>Groussin, Lionel</au><au>Borson-Chazot, Françoise</au><au>Coste, Joël</au><au>Bertagna, Xavier</au><au>Stratakis, Constantine A</au><au>Beuschlein, Felix</au><au>Ragazzon, Bruno</au><au>Bertherat, Jérôme</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences</atitle><jtitle>The journal of clinical endocrinology and metabolism</jtitle><addtitle>J Clin Endocrinol Metab</addtitle><date>2015-06</date><risdate>2015</risdate><volume>100</volume><issue>6</issue><spage>E926</spage><epage>E935</epage><pages>E926-E935</pages><issn>0021-972X</issn><eissn>1945-7197</eissn><abstract>Context:
Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of primary adrenal Cushing's syndrome (CS). ARMC5 germline mutations have been identified recently in PBMAH.
Objective:
To determine the prevalence of ARMC5 mutations and analyze genotype-phenotype correlation in a large cohort of unrelated PBMAH patients with subclinical or clinical CS.
Patients and Methods:
ARMC5 was sequenced in 98 unrelated PBMAH index cases. PBMAH was identified by bilateral adrenal nodular enlargement on computed tomography scan. The effect on apoptosis of ARMC5 missense mutants was tested in H295R and HeLa cells. Clinical and hormonal data were collected including midnight and urinary free cortisol levels, ACTH, androgens, renin/aldosterone ratio, cortisol after overnight dexamethasone suppression test, cortisol and 17-hydroxyprogesterone after ACTH 1-24 stimulation and illegitimate receptor responses. Computed tomography and histological reports were analyzed.
Results:
ARMC5-damaging mutations were identified in 24 patients (26%). The missense mutants and the p.F700del deletion were unable to induce apoptosis in both H295R and HeLa cell lines, unlike the wild-type gene. ARMC5-mutated patients showed an overt CS more frequently, compared to wild-type patients: lower ACTH, higher midnight plasma cortisol, urinary free cortisol, and cortisol after dexamethasone suppression test (P = .003, .019, .006, and <.001, respectively). Adrenals of patients with mutations were bigger and had a higher number of nodules (P = .001 and <.001, respectively).
Conclusions:
ARMC5 germline mutations are common in PBMAH. Index cases of mutation carriers show a more severe hypercortisolism and larger adrenals. ARMC5 genotyping may help to identify clinical forms of PBMAH better and may also allow earlier diagnosis of this disease.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>25853793</pmid><doi>10.1210/jc.2014-4204</doi><orcidid>https://orcid.org/0000-0001-7826-3984</orcidid><orcidid>https://orcid.org/0000-0001-9476-4973</orcidid><orcidid>https://orcid.org/0000-0001-9590-0906</orcidid><orcidid>https://orcid.org/0000-0003-2515-7840</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Journals@Ovid Complete; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Adrenal Cortex Diseases Adrenal Cortex Diseases - epidemiology Adrenal Cortex Diseases - genetics Adrenal Glands Adrenal Glands - pathology Adult Aged Cells, Cultured Cohort Studies Cushing Syndrome Cushing Syndrome - epidemiology Cushing Syndrome - genetics DNA Mutational Analysis Female Genetic Association Studies HeLa Cells Humans Hyperplasia Hyperplasia - genetics Hyperplasia - pathology JCEM Online: Advances in Genetics Life Sciences Male Middle Aged Mutation, Missense Santé publique et épidémiologie Tumor Suppressor Proteins Tumor Suppressor Proteins - genetics |
| title | ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences |
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