Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter.
| Title: | Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. |
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| Authors: | Åkerström T; Department of Surgical Sciences, Genetics and Pathology, Uppsala University, Uppsala, Sweden.; Crona J; Delgado Verdugo A; Starker LF; Cupisti K; Willenberg HS; Knoefel WT; Saeger W; Feller A; Ip J; Soon P; Anlauf M; Alesina PF; Schmid KW; Decaussin M; Levillain P; Wängberg B; Peix JL; Robinson B; Zedenius J; Bäckdahl M; Caramuta S; Iwen KA; Botling J; Stålberg P; Kraimps JL; Dralle H; Hellman P; Sidhu S; Westin G; Lehnert H; Walz MK; Åkerström G; Carling T; Choi M; Lifton RP; Björklund P |
| Source: | PloS one [PLoS One] 2012; Vol. 7 (7), pp. e41926. Date of Electronic Publication: 2012 Jul 27. |
| Publication Type: | Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: San Francisco, CA : Public Library of Science |
| MeSH Terms: | Mutation* ; Sequence Analysis*; Adrenal Cortex Neoplasms/*genetics ; Adrenocortical Adenoma/*genetics ; Aldosterone/*biosynthesis; Adrenal Cortex Neoplasms/metabolism ; Adrenocortical Adenoma/metabolism ; Adolescent ; Adult ; Aged ; Base Sequence ; Cohort Studies ; DNA Mutational Analysis ; Female ; Humans ; Male ; Middle Aged ; Mutation Rate ; Sex Characteristics ; Young Adult |
| 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 |
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| Grant Information: | P30 DK079310 United States DK NIDDK NIH HHS |
| Substance Nomenclature: | 4964P6T9RB (Aldosterone) |
| Entry Date(s): | Date Created: 20120801 Date Completed: 20130110 Latest Revision: 20211021 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC3407065 |
| DOI: | 10.1371/journal.pone.0041926 |
| PMID: | 22848660 |
| Database: | MEDLINE |
Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't