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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.

plos one

Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter