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

被引:143
作者
Akerstrom, Tobias [1 ]
Crona, Joakim [1 ]
Verdugo, Alberto Delgado [1 ]
Starker, Lee F. [1 ,2 ]
Cupisti, Kenko [3 ]
Willenberg, Holger S. [7 ]
Knoefel, Wolfram T. [3 ]
Saeger, Wolfgang [19 ]
Feller, Alfred [18 ]
Ip, Julian [11 ,12 ]
Soon, Patsy [11 ,12 ,23 ]
Anlauf, Martin [8 ]
Alesina, Pier F. [13 ,14 ]
Schmid, Kurt W. [15 ]
Decaussin, Myriam [16 ]
Levillain, Pierre [21 ]
Wangberg, Bo [22 ]
Peix, Jean-Louis [17 ]
Robinson, Bruce [11 ,12 ]
Zedenius, Jan [5 ]
Backdahl, Martin [5 ]
Caramuta, Stefano [6 ]
Iwen, K. Alexander [20 ]
Botling, Johan [9 ]
Stalberg, Peter [1 ]
Kraimps, Jean-Louis
Dralle, Henning [4 ]
Hellman, Per [1 ]
Sidhu, Stan [11 ,12 ]
Westin, Gunnar [1 ]
Lehnert, Hendrik [20 ]
Walz, Martin K. [13 ,14 ]
Akerstrom, Goran [1 ]
Carling, Tobias [2 ]
Choi, Murim [10 ]
Lifton, Richard P. [10 ]
Bjorklund, Peyman [1 ]
机构
[1] Uppsala Univ, Dept Surg Sci Genet & Pathol, Uppsala, Sweden
[2] Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USA
[3] Univ Hosp Dusseldorf, Dept Gen Visceral & Pediat Surg, Dusseldorf, Germany
[4] Univ Halle Wittenberg, Univ Hosp, Dept Gen Visceral & Vasc Surg, Halle, Germany
[5] Karolinska Inst, Karolinska Univ Hosp, Endocrine Surg Unit, Dept Mol Med & Surg, Stockholm, Sweden
[6] Karolinska Inst, Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden
[7] Univ Hosp Dusseldorf, Dept Endocrinol Diabet & Rheumatol, Dusseldorf, Germany
[8] Univ Hosp Dusseldorf, Inst Pathol, Dusseldorf, Germany
[9] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden
[10] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA
[11] Royal N Shore Hosp, Kolling Inst Med Res, Canc Genet Hormones & Canc Grp, Sydney, NSW, Australia
[12] Univ Sydney, Endocrine Surg Unit, Sydney, NSW 2006, Australia
[13] Univ Duisburg Essen, Kliniken Essen Mitte, Klin Chirurg, Essen, Germany
[14] Univ Duisburg Essen, Kliniken Essen Mitte, Zentrum Minimal Invas Chirurg, Essen, Germany
[15] Univ Duisburg Essen, Univ Klinikum, Inst Pathol & Neuropathol, Essen, Germany
[16] Ctr Hosp Lyon Sud, Dept Pathol, Lyon, France
[17] Ctr Hosp Lyon Sud, Dept Endocrine Surg, Lyon, France
[18] Univ Hosp Lubeck, Dept Pathol, Lubeck, Germany
[19] Marien Hosp, Dept Pathol, Hamburg, Germany
[20] Univ Klinikum Schleswig Holstein, Med Klin, D-23538 Lubeck, Germany
[21] Ctr Hosp Poitiers, Dept Pathol, Poitiers, France
[22] Univ Gothenburg, Sahlgrenska Akad, Gothenburg, Sweden
[23] Univ New S Wales, S Western Sydney Clin Sch, Bankstown Hosp, Dept Surg, Sydney, NSW, Australia
来源
PLOS ONE | 2012年 / 7卷 / 07期
基金
瑞典研究理事会;
关键词
HYPERTENSION; DIAGNOSIS; HYPERPLASIA; ADENOMAS;
D O I
10.1371/journal.pone.0041926
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:7
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