ARMC5 mutations are a frequent cause of primary macronodular adrenal Hyperplasia.
BACKGROUND
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.


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.
Unidade de Suprarrenal (G.A.A., A.M.L., M.Y.N., B.M.d.P.M., M.Q.A., M.A.A.P., B.B.M., M.C.B.V.F.), Disciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403900, Brazil; Département de Médecine (J.T., P.H., I.B., A.L.), Centre Hospitalier de l'Université de Montréal, Montréal H2W 1T8, Canada; Departamento de Patologia (M.C.N.Z.), Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403900, Brazil; Departamento de Radiologia (G.C.G., M.d.S.R.), Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403900, Brazil; and Disciplina de Urologia, Departamento de Cirurgia (J.L.C.), Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403900, Brazil.
Guilherme Asmar
GA
Alencar
Antonio Marcondes
AM
Lerario
Mirian Yumie
MY
Nishi
Beatriz Marinho de Paula
BM
Mariani
Madson Queiroz
MQ
Almeida
Johanne
J
Tremblay
Pavel
P
Hamet
Isabelle
I
Bourdeau
Maria Claudia Nogueira
MC
Zerbini
Maria Adelaide Albergaria
MA
Pereira
Gilberto Carlos
GC
Gomes
Manoel de Souza
Mde S
Rocha
Jose Luis
JL
Chambo
André
A
Lacroix
Berenice Bilharinho
BB
Mendonca
Maria Candida Barisson Villares
MC
Fragoso
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051186:Armadillo Domain Proteins; D001938:Brazil; D003480:Cushing Syndrome / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C000590373:ARMC5 protein, human; D051186:Armadillo Domain Proteins; D025521:Tumor Suppressor Proteins