Novel gain-of-function CLCN2 germline mutation associated with nonclassical lateralizing primary aldosteronism

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Primary aldosteronism (PA) is often caused by gene mutations.
• Unilateral PA can present with classical or nonclassical adrenal tumor histopathology.
• Novel gene mutations causing nonclassical PA require identification.

Purpose of the Study:

• To identify novel gene mutations responsible for nonclassical lateralizing primary aldosteronism.
• To investigate the pathogenic mechanisms of identified variants in adrenal cells.

Main Methods:

• Histopathologic evaluation of surgically resected adrenal tumors.
• Genetic analysis of DNA from blood and adrenal tissues.
• In vitro functional assays (biochemical, electrophysiological, hormone) of identified variants.

Main Results:

• A heterozygous CLCN2 germline variant (c.1087C>T, p.R363C) was identified in a PA patient with nonclassical multiple aldosterone-producing micronodules (mAPM).
• The ClC-2 R363C variant demonstrated gain-of-function properties in vitro, including increased stability, cell surface expression, channel activity, and aldosterone production.
• A dominant gain-of-function effect was observed when co-expressed with wild-type CLCN2.

Conclusions:

• This study reports the first association of a gain-of-function CLCN2 germline mutation with nonclassical mAPM in primary aldosteronism.
• The findings provide novel insights into the molecular mechanisms underlying PA development.
• CLCN2 variants represent a new genetic cause for nonclassical primary aldosteronism.