ARMC5 Mutations Are a Frequent Cause of Primary Macronodular Adrenal Hyperplasia

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dc.contributor Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.author ALENCAR, Guilherme Asmar FMUSP-HC
LERARIO, Antonio Marcondes FMUSP-HC
NISHI, Mirian Yumie FMUSP-HC
MARIANI, Beatriz Marinho de Paula FMUSP-HC
ALMEIDA, Madson Queiroz FMUSP-HC
TREMBLAY, Johanne
HAMET, Pavel
BOURDEAU, Isabelle
ZERBINI, Maria Claudia Nogueira FMUSP-HC
PEREIRA, Maria Adelaide Albergaria FMUSP-HC
GOMES, Gilberto Carlos FMUSP-HC
ROCHA, Manoel de Souza FMUSP-HC
CHAMBO, Jose Luis FMUSP-HC
LACROIX, Andre
MENDONCA, Berenice Bilharinho FMUSP-HC
FRAGOSO, Maria Candida Barisson Villares FMUSP-HC
dc.date.issued 2014
dc.identifier.citation JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v.99, n.8, p.E1501-E1509, 2014
dc.identifier.issn 0021-972X
dc.identifier.uri http://observatorio.fm.usp.br/handle/OPI/8630
dc.description.abstract Context: Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, usually characterized by functioning adrenal macronodules and increased cortisol production. Familial clustering of PMAH has been described, suggesting an inherited genetic cause for this condition. Objective: The aim of the present study was to identify the gene responsible for familial PMAH. Patients and Methods: Forty-seven individuals of a Brazilian family with PMAH were evaluated. A single-nucleotide polymorphism-based genome-wide linkage analysis followed by whole-exome sequencing were then performed in selected family members. Additionally, 29 other patients with PMAH and 125 randomly selected healthy individuals were studied to validate the genetic findings. Moreover, PMAH tissue was also analyzed through whole-exome sequencing, conventional sequencing, and microsatellite analysis. Results: A heterozygous germline variant in the ARMC5 gene (p.Leu365Pro) was identified by whole-exome sequencing in a candidate genomic region (16p11.2). Subsequently, the same variant was confirmed by conventional sequencing in all 16 affected family members. The variant was predicted to be damaging by in silico methods and was not found in available online databases or in the 125 selected healthy individuals. Seven additional ARMC5 variants were subsequently identified in 5 of 21 patients with apparently sporadic PMAH and in 2 of 3 families with the disease. Further molecular analysis identified a somatic mutational event in 4 patients whose adrenal tissue was available. Conclusions: Inherited autosomal dominant mutations in the ARMC5 gene are a frequent cause of PMAH. Biallelic inactivation of ARMC5 is consistent with its role as a potential tumor suppressor gene.
dc.description.sponsorship · Sao Paulo Research Foundation (FAPESP) [2010/12702-1]
· Brazilian fostering agency Coordination for the Improvement of Higher Education Personnel
· genome-wide linkage study platform at Centre Hospitalier de l'Universite de Montreal research center
dc.language.iso eng
dc.publisher ENDOCRINE SOC
dc.relation.ispartof Journal of Clinical Endocrinology & Metabolism
dc.rights restrictedAccess
dc.subject.other independent cushings-syndrome; gastric-inhibitory polypeptide; protein function; vasopressin; glands; receptors; corticotropin; heterogeneity; expression; secretion
dc.title ARMC5 Mutations Are a Frequent Cause of Primary Macronodular Adrenal Hyperplasia
dc.type article
dc.rights.holder Copyright ENDOCRINE SOC
dc.description.group LIM/42
dc.description.group LIM/14
dc.identifier.doi 10.1210/jc.2013-4237
dc.type.category original article
dc.type.version publishedVersion
hcfmusp.author ALENCAR, Guilherme Asmar:FM:
hcfmusp.author LERARIO, Antonio Marcondes:HC:LIM/42
hcfmusp.author NISHI, Mirian Yumie:HC:LIM/42
hcfmusp.author MARIANI, Beatriz Marinho de Paula:FM:
hcfmusp.author ALMEIDA, Madson Queiroz:HC:LIM/42
hcfmusp.author ZERBINI, Maria Claudia Nogueira:FM:MPT
hcfmusp.author PEREIRA, Maria Adelaide Albergaria:HC:ICHC
hcfmusp.author GOMES, Gilberto Carlos:HC:INRAD
hcfmusp.author ROCHA, Manoel de Souza:FM:MDR
hcfmusp.author CHAMBO, Jose Luis:HC:ICHC
hcfmusp.author MENDONCA, Berenice Bilharinho:FM:MCM
hcfmusp.author FRAGOSO, Maria Candida Barisson Villares:HC:LIM/42
hcfmusp.author.external · TREMBLAY, Johanne:Univ Montreal, Ctr Hosp, Dept Med, Montreal, PQ H2W 1T8, Canada
· HAMET, Pavel:Univ Montreal, Ctr Hosp, Dept Med, Montreal, PQ H2W 1T8, Canada
· BOURDEAU, Isabelle:Univ Montreal, Ctr Hosp, Dept Med, Montreal, PQ H2W 1T8, Canada
· LACROIX, Andre:Univ Montreal, Ctr Hosp, Dept Med, Montreal, PQ H2W 1T8, Canada
hcfmusp.origem.id 2-s2.0-84905828393
hcfmusp.origem.id WOS:000342341200015
hcfmusp.publisher.city WASHINGTON
hcfmusp.publisher.country USA
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dc.description.index MEDLINE
dc.identifier.eissn 1945-7197
hcfmusp.citation.scopus 66
hcfmusp.citation.wos 53
hcfmusp.affiliation.country Brasil
hcfmusp.affiliation.country Canadá


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