What is the genetic basis of unilateral aldosterone-producing adrenal adenomas (APA, familial hyperaldosteronism type 3)?
The etiology of APA is de novo, somatic mutations in adrenal zona glomerulosa cells. Exome sequencing from adrenal adenoma tissues identified that ∼30% of APA are due to somatic mutations in one gene, the inwardly rectifying potassium channel KCNJ5, causing amino acid substitutions in one of two highly conserved residues (G151R and L168R). In vitro experiments suggest that these rare somatic mutations lead to chronic depolarization of adrenal cells, causing constitutive aldosterone production as well as adrenal cell proliferation and unilateral adenoma. Interestingly, KCNJ5 mutations occur approximately twice as often in female than male individuals with APA. Also of interest, one rare genomic KCNJ5 mutation (T158A), transmitted in autosomal-dominant fashion, was identified in one family with bilateral familial adrenal adenomas associated with severe hypertension.
Less common APA-causing somatic mutations in other genes are more frequently seen in males, including ATP1A1 (Na/K ATPase α1 subunit) and ATP2B (Ca++ ATPase). The causes for these gender differences are unknown; hormonal differences could play a role. Another gene implicated in APA is CACNA1D (a voltage-gated calcium channel); affected individuals feature seizures and other neurological abnormalities. Additional, rarer APA genes have been recently identified.