A somatic mutation in CLCN2 identified in a sporadic aldosterone-producing adenoma

in European Journal of Endocrinology
Correspondence should be addresed to P Söderkvist; Email: peter.soderkvist@liu.se

*P Söderkvist and O Gimm contributed equally to this work

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Objective

To screen for CLCN2 mutations in apparently sporadic cases of aldosterone-producing adenomas (APAs).

Description

Recently, CLCN2, encoding for the voltage-gated chloride channel protein 2 (ClC-2), was identified to be mutated in familial hyperaldosteronism II (FH II). So far, somatic mutations in CLCN2 have not been reported in sporadic cases of APAs. We screened 80 apparently sporadic APAs for mutations in CLCN2. One somatic mutation was identified at p.Gly24Asp in CLCN2. The male patient had a small adenoma in size but high aldosterone levels preoperatively. Postoperatively, the patient had normal aldosterone levels and was clinically cured.

Conclusion

In this study, we identified a CLCN2 mutation in a sporadic APA comprising about 1% of all APAs investigated. This mutation was complementary to mutations in other susceptibility genes for sporadic APAs and may thus be a driving mutation in APA formation.

 

     European Society of Endocrinology

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    CLCN2 mutations and comparison of pre-clinical and clinical variables. Sequencing chromatograms showing (A) the somatic mutation c.71G>A in a sporadic APA (top) and wild-type CLCN2 sequence in blood (bottom) and (B) the germline variant c.218G>A in both the APA (top) and blood (bottom). (C) Position of the identified somatic mutation (yellow dot) on the protein structure of the CIC-2 channel. (D) Amino acid sequence alignment of human CIC-2 channel with its orthologs. Arrow indicates the identified mutation in this study. (E) A somatic CLCN2 variant was found in 1 out of 39 sporadic APAs (primary cohort). This mutation is complementary to 20 other mutations in KCNJ5, ATP1A1, ATP2B3, CTNNB1 and CACNA1D. The remaining 18 APAs had no identified mutations in the listed susceptibility genes. (F) Log10 expression of CLCN2 after normalization of mRNA microarray data (unpublished data). (G) Relative mRNA levels of CYP11B2 in tumors with different mutations (real-time qPCR analysis of total RNA using HPRT1 as an internal control). (H) Plasma aldosterone levels in patients with different mutations (indicated on graph) and without mutation in the known susceptibility genes. (I) Age of the patients and (J) diameter of the tumors with regard to the identified mutation. neg, no mutation found.

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