title: Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter.
abstract: BACKGROUND
  Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na(+) conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.
  
  
  METHODS
  The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.
  
  
  RESULTS
  G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005).
  
  
  CONCLUSIONS
  Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.
authors: Department of Surgical Sciences, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors: Tobias
authors: T
authors: Åkerström
authors: Joakim
authors: J
authors: Crona
authors: Alberto
authors: A
authors: Delgado Verdugo
authors: Lee F
authors: LF
authors: Starker
authors: Kenko
authors: K
authors: Cupisti
authors: Holger S
authors: HS
authors: Willenberg
authors: Wolfram T
authors: WT
authors: Knoefel
authors: Wolfgang
authors: W
authors: Saeger
authors: Alfred
authors: A
authors: Feller
authors: Julian
authors: J
authors: Ip
authors: Patsy
authors: P
authors: Soon
authors: Martin
authors: M
authors: Anlauf
authors: Pier F
authors: PF
authors: Alesina
authors: Kurt W
authors: KW
authors: Schmid
authors: Myriam
authors: M
authors: Decaussin
authors: Pierre
authors: P
authors: Levillain
authors: Bo
authors: B
authors: Wängberg
authors: Jean-Louis
authors: JL
authors: Peix
authors: Bruce
authors: B
authors: Robinson
authors: Jan
authors: J
authors: Zedenius
authors: Martin
authors: M
authors: Bäckdahl
authors: Stefano
authors: S
authors: Caramuta
authors: K Alexander
authors: KA
authors: Iwen
authors: Johan
authors: J
authors: Botling
authors: Peter
authors: P
authors: Stålberg
authors: Jean-Louis
authors: JL
authors: Kraimps
authors: Henning
authors: H
authors: Dralle
authors: Per
authors: P
authors: Hellman
authors: Stan
authors: S
authors: Sidhu
authors: Gunnar
authors: G
authors: Westin
authors: Hendrik
authors: H
authors: Lehnert
authors: Martin K
authors: MK
authors: Walz
authors: Göran
authors: G
authors: Åkerström
authors: Tobias
authors: T
authors: Carling
authors: Murim
authors: M
authors: Choi
authors: Richard P
authors: RP
authors: Lifton
authors: Peyman
authors: P
authors: Björklund
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism; D018246:Adrenocortical Adenoma / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000096:biosynthesis*; D001483:Base Sequence; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D017421:Sequence Analysis; D012727:Sex Characteristics; D055815:Young Adult
chemical_list: D000450:Aldosterone