Do KCNJ5 mutations promote abnormal adrenocortical cell proliferation in APA?

Determine whether somatic KCNJ5 mutations in aldosterone-producing adenoma cells directly promote abnormal adrenocortical cell proliferation in addition to autonomous aldosterone biosynthesis, and identify the cellular or developmental contexts under which such proliferative effects, if any, occur.

Background

Somatic mutations in KCNJ5, which encodes the GIRK4 potassium channel, are the most frequent genetic alterations in aldosterone-producing adenomas. These mutations increase sodium influx, depolarize the membrane, open voltage-gated calcium channels, and elevate intracellular calcium, thereby stimulating CYP11B2 expression and aldosterone production.

While this aldosterone phenotype is well established, evidence for a direct proliferative role of KCNJ5 mutations is conflicting. In the presented chemogenetic model that reproduces sodium entry and downstream calcium signaling, the authors observe decreased proliferation and increased apoptosis, suggesting that additional events may be required for adenoma development. Clarifying whether KCNJ5 alone can drive abnormal proliferation remains essential for understanding APA pathogenesis.