ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome.

[cushing syndrome]

Corticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing 's syndrome . Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition .We genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age ), using single -nucleotide polymorphism arrays , microsatellite markers , and whole-genome and Sanger sequencing . The effects of armadillo repeat containing 5 (ARMC 5 ) inactivation and overexpression were tested in cell-culture models .The most frequent somatic chromosome alteration was loss of heterozygosity at 16 p (in 8 of 33 patients for whom data were available [24 %]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC 5 , located at 16 p 11 .2 . ARMC 5 mutations were detected in tumors obtained from 18 of 33 patients (55 %). In all cases , both alleles of ARMC 5 carried mutations : one germline and the other somatic . In 4 patients with a germline ARMC 5 mutation , different nodules from the affected adrenals harbored different secondary ARMC 5 alterations . Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC 5 mutations influenced gene expression , since all cases with mutations clustered together . ARMC 5 inactivation decreased steroidogenesis in vitro , and its overexpression altered cell survival .Some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic , most often with inactivating mutations of ARMC 5 , a putative tumor -suppressor gene . Genetic testing for this condition , which often has a long and insidious prediagnostic course , might result in earlier identification and better management . (Funded by Agence Nationale de la Recherche and others .).

Diseases
Validation

Diseases presenting "frequent mutation" symptom

adrenomyeloneuropathy

cushing syndrome

cutaneous mastocytosis

familial mediterranean fever

neonatal adrenoleukodystrophy

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