ATP1A1 – Primary Aldosteronism

Primary aldosteronism (PA) is the leading cause of secondary hypertension, most frequently due to unilateral aldosterone-producing adenomas (APAs). Somatic mutations in ion transporter genes, including ATP1A1, underlie aberrant aldosterone secretion in a subset of APAs, providing insight into tumorigenesis and potential targets for precision therapy.

In large cohort studies, ATP1A1 somatic variants were identified in 25 of 474 APAs (5.3%) in European patients and in 16 of 308 APAs (5.2%) in a multi-center collection (PMID:24866132) (PMID:23416519). Additional series from Taiwan and other populations report mutation frequencies of approximately 1.4–6.3%, confirming recurrent involvement of ATP1A1 in PA pathogenesis.

The variant spectrum in ATP1A1 is dominated by recurrent missense changes in the ion-binding domain, most notably c.311T>G (p.Leu104Arg), as well as small in-frame deletions affecting residues 100–104. These hotspots occur in a heterozygous state and cluster in the transmembrane segment that regulates Na+/K+-ATPase conformation and ion transport.

Functional assays demonstrate that ATP1A1 mutations impair pump activity, reduce potassium affinity, and induce membrane depolarization, driving constitutive aldosterone synthase (CYP11B2) expression and autonomous hormone production in adrenal cells (PMID:23416519). Electrophysiological studies on primary tumor cells corroborate inappropriate depolarization and elevated aldosterone output.

Clinically, ATP1A1-mutant APA patients show male predominance, higher plasma aldosterone, lower serum potassium, and more pronounced hypokalemia compared to noncarriers. Post-operative cure rates of hypertension are favorable in mutation carriers, supporting the diagnostic and prognostic value of ATP1A1 genotyping.

No germline segregation of ATP1A1 in familial PA has been reported; all mutations are somatic. There are no studies disputing the role of ATP1A1 variants in APA development. Taken together, abundant case series, multi-center replication, and concordant functional data support a Strong ClinGen classification for the ATP1A1–primary aldosteronism association.

Key Take-Home: Somatic ATP1A1 mutations in ~5% of APAs cause Na+/K+-ATPase dysfunction and autonomous aldosterone secretion, offering a robust diagnostic marker and informing targeted management of primary aldosteronism.

References

• Hypertension (Dallas, Tex. : 1979) • 2014 • Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma. PMID:24866132
• Nature Genetics • 2013 • Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. PMID:23416519

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