Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
Show others and affiliations
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.

Place, publisher, year, edition, pages
2012. Vol. 7, no 7, e41926- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-183242DOI: 10.1371/journal.pone.0041926ISI: 000306950200128OAI: oai:DiVA.org:uu-183242DiVA: diva2:562594
Available from: 2012-10-25 Created: 2012-10-23 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Genetic Alterations in Aldosterone Producing Adenomas
Open this publication in new window or tab >>Genetic Alterations in Aldosterone Producing Adenomas
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:nbn:se:uu:diva-219929 (URN)
Presentation
2014-03-21, 13:15 (English)
Opponent
Supervisors
Available from: 2014-03-10 Created: 2014-03-07 Last updated: 2014-07-24Bibliographically approved
2. Genetic Alterations and Molecular Signatures in Aldosterone Producing Adenomas
Open this publication in new window or tab >>Genetic Alterations and Molecular Signatures in Aldosterone Producing Adenomas
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Primary Aldosteronism (PA) is caused by autonomous overproduction of aldosterone. Aldosterone is necessary for fluid and ion homeostasis. Aberrant overproduction leads to hypertension and cardiovascular damage. With a prevalence of over 5% in the worlds’ hypertensive community, and with over a billion people worldwide having high blood pressure, PA represents a major contributor to health care costs and morbidity. Importantly, 30% of PA patients have a unilateral dominant secretion, an aldosterone producing adenoma (APA), making it possible to cure a substantial portion of patients with surgery. Unfortunately, there is a large underdiagnosis of PA, leading to delayed diagnosis in many patients, worsening their outcome after surgery. A need for better screening techniques, raised awareness and treatment options for PA is warranted.

Since 2011, the genetic understanding of APAs has revolutionized. Somatic mutations turning on an autonomous aldosterone production has been observed in up to 80% of tumors. In this thesis we have investigated the genetic landscape and phenotypes of APAs. By international collaborations we have collected one of the largest cohorts of APAs ever sequenced. We have confirmed and extended the understanding of KCNJ5 mutations, its associated phenotype and the specificity for APAs. We have confirmed a high rate of mutations in ATP1A1, ATP2B3 and CACNA1D, and noted distinct clinical and molecular phenotypes in these tumors. We describe a marker of Zona Glomerulosa cells, perhaps important for the normal regulation and function of these cells. We observe somatic mutations in CTNNB1, occurring in a mutually exclusive manner to the other mutations. Using in situ sequencing, we note genetic heterogeneity in APAs with KCNJ5 mutations. Finally, we evaluate intratumoral aldosterone measurement on a large cohort of tumors, validating a high specificity for APAs. Noting also a difference in the level of intratumoral aldosterone between APAs and a possible association with genotype. Remarkably, we also note a robust correlation between the intracellular concentrations and plasma-aldosterone. We hope that with gained knowledge of the genetic background, the understanding of both pathologic and normal states of the adrenals will increase, and hopefully benefit patients in the future.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1197
Keyword
Aldosterone, aldosterone producing adenoma, KCNJ5, ATP1A1, ATP2B3, CACNA1D, CTNNB1
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-281042 (URN)978-91-554-9517-6 (ISBN)
Public defence
2016-05-07, Robergssalen, Akademiska sjukhuset, ingång 40, plan 4, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2016-04-15 Created: 2016-03-16 Last updated: 2016-04-21

Open Access in DiVA

fulltext(367 kB)340 downloads
File information
File name FULLTEXT01.pdfFile size 367 kBChecksum SHA-512
06cec110b41c9599916246afa1a435c735ec44c7f60e8c0a7760093b0f88a5fd30b2b7b78fc8f9baf6f4ee621222cd4387fabd16c62c4f759290012ff272d2c0
Type fulltextMimetype application/pdf

Other links

Publisher's full text

Search in DiVA

By author/editor
Åkerström, TobiasCrona, JoakimVerdugo, Alberto DelgadoStarker, Lee F.Botling, JohanStålberg, PeterHellman, PerWestin, GunnarÅkerström, GöranBjörklund, Peyman
By organisation
Experimental SurgeryMolecular and Morphological PathologyEndocrine Surgery
In the same journal
PLoS ONE
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 340 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 955 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf