title: Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism.
abstract: Primary aldosteronism is the most common form of secondary hypertension. Mutations in the KCNJ5 gene have been described recently in aldosterone-producing adenomas (APAs). The aim of this study was to investigate the prevalence of KCNJ5 mutations in unselected patients with primary aldosteronism and their clinical, biological and molecular correlates. KCNJ5 sequencing was performed on somatic (APA, n=380) and peripheral (APA, n=344; bilateral adrenal hyperplasia, n=174) DNA of patients with primary aldosteronism, collected through the European Network for the Study of Adrenal Tumors. Transcriptome analysis was performed in 102 tumors. Somatic KCNJ5 mutations (p.Gly151Arg or p.Leu168Arg) were found in 34% (129 of 380) of APA. They were significantly more prevalent in females (49%) than males (19%; P<10(-3)) and in younger patients (42.1±1.0 versus 47.6±0.7 years; P<10(-3)) and were associated with higher preoperative aldosterone levels (455±26 versus 376±17 ng/L; P=0.012) but not with therapeutic outcome after surgery. Germline KCNJ5 mutations were found neither in patients with APA nor those with bilateral adrenal hyperplasia. Somatic KCNJ5 mutations were specific for APA, because they were not identified in 25 peritumoral adrenal tissues or 16 cortisol-producing adenomas. Hierarchical clustering of transcriptome profiles showed that APAs with p.Gly151Arg or p.Leu168Arg mutations were indistinguishable from tumors without KCNJ5 mutations. In conclusion, although a large proportion of sporadic APAs harbors somatic KCNJ5 mutations, germline mutations are not similarly causative for bilateral adrenal hyperplasia. KCNJ5 mutation carriers are more likely to be females; younger age and higher aldosterone levels at diagnosis suggest that KCNJ5 mutations may be associated with a more florid phenotype of primary aldosteronism.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique 970, Paris Cardiovascular Research Center, Paris, France.
authors.forename: Sheerazed
authors.initials: S
authors.lastname: Boulkroun
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
authors.forename: Gian-Paolo
authors.initials: GP
authors.lastname: Rossi
authors.forename: José-Felipe
authors.initials: JF
authors.lastname: Golib-Dzib
authors.forename: Evelyn
authors.initials: E
authors.lastname: Fischer
authors.forename: Laurence
authors.initials: L
authors.lastname: Amar
authors.forename: Paolo
authors.initials: P
authors.lastname: Mulatero
authors.forename: Benoit
authors.initials: B
authors.lastname: Samson-Couterie
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hahner
authors.forename: Marcus
authors.initials: M
authors.lastname: Quinkler
authors.forename: Francesco
authors.initials: F
authors.lastname: Fallo
authors.forename: Claudio
authors.initials: C
authors.lastname: Letizia
authors.forename: Bruno
authors.initials: B
authors.lastname: Allolio
authors.forename: Giulio
authors.initials: G
authors.lastname: Ceolotto
authors.forename: Maria Verena
authors.initials: MV
authors.lastname: Cicala
authors.forename: Katharina
authors.initials: K
authors.lastname: Lang
authors.forename: Hervé
authors.initials: H
authors.lastname: Lefebvre
authors.forename: Livia
authors.initials: L
authors.lastname: Lenzini
authors.forename: Carmela
authors.initials: C
authors.lastname: Maniero
authors.forename: Silvia
authors.initials: S
authors.lastname: Monticone
authors.forename: Maelle
authors.initials: M
authors.lastname: Perrocheau
authors.forename: Catia
authors.initials: C
authors.lastname: Pilon
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Plouin
authors.forename: Nada
authors.initials: N
authors.lastname: Rayes
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Seccia
authors.forename: Franco
authors.initials: F
authors.lastname: Veglio
authors.forename: Tracy Ann
authors.initials: TA
authors.lastname: Williams
authors.forename: Laura
authors.initials: L
authors.lastname: Zinnamosca
authors.forename: Franco
authors.initials: F
authors.lastname: Mantero
authors.forename: Arndt
authors.initials: A
authors.lastname: Benecke
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Martin
authors.initials: M
authors.lastname: Reincke
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Zennaro
mesh_terms: D000328:Adult; D000450:Aldosterone / Q000097:blood*; D005260:Female; D005500:Follow-Up Studies; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000097:blood / Q000235:genetics*; D006801:Humans; D006929:Hyperaldosteronism / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D015995:Prevalence; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D000450:Aldosterone; D012313:RNA