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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.

Materials and 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).

Discussion

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.

SUBMITTER: Akerstrom T 

PROVIDER: S-EPMC3407065 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter.

Åkerström Tobias T   Crona Joakim J   Delgado Verdugo Alberto A   Starker Lee F LF   Cupisti Kenko K   Willenberg Holger S HS   Knoefel Wolfram T WT   Saeger Wolfgang W   Feller Alfred A   Ip Julian J   Soon Patsy P   Anlauf Martin M   Alesina Pier F PF   Schmid Kurt W KW   Decaussin Myriam M   Levillain Pierre P   Wängberg Bo B   Peix Jean-Louis JL   Robinson Bruce B   Zedenius Jan J   Bäckdahl Martin M   Caramuta Stefano S   Iwen K Alexander KA   Botling Johan J   Stålberg Peter P   Kraimps Jean-Louis JL   Dralle Henning H   Hellman Per P   Sidhu Stan S   Westin Gunnar G   Lehnert Hendrik H   Walz Martin K MK   Åkerström Göran G   Carling Tobias T   Choi Murim M   Lifton Richard P RP   Björklund Peyman P  

PloS one 20120727 7


<h4>Background</h4>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  ...[more]

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