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Genetic Alterations in Aldosterone Producing Adenomas
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. (Experimentell kirurgi)
2014 (English)Licentiate thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Uppsala: Uppsala University, Department of Surgical Sciences , 2014. , 67 p.
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-219929OAI: oai:DiVA.org:uu-219929DiVA: diva2:703570
Presentation
2014-03-21, 13:15 (English)
Opponent
Supervisors
Available from: 2014-03-10 Created: 2014-03-07 Last updated: 2014-07-24Bibliographically approved
List of papers
1. Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
Open this publication in new window or tab >>Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, e41926- p.Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-183242 (URN)10.1371/journal.pone.0041926 (DOI)000306950200128 ()
Available from: 2012-10-25 Created: 2012-10-23 Last updated: 2017-12-07Bibliographically approved
2. Activating Mutations in CTNNB1 in Aldosterone Producing Adenomas
Open this publication in new window or tab >>Activating Mutations in CTNNB1 in Aldosterone Producing Adenomas
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(English)Manuscript (preprint) (Other academic)
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-218662 (URN)
Available from: 2014-02-13 Created: 2014-02-13 Last updated: 2015-06-26Bibliographically approved
3. Somatic Mutations in ATP1A1 and ATP2B3 in Aldosterone Producing Adenomas
Open this publication in new window or tab >>Somatic Mutations in ATP1A1 and ATP2B3 in Aldosterone Producing Adenomas
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(English)Manuscript (preprint) (Other academic)
Keyword
ATP1A1, ATP2B3, Aldosterone producing adenomas, Mutation, KCNJ5
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-218659 (URN)
Available from: 2014-02-13 Created: 2014-02-13 Last updated: 2014-03-11

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