OR02-01 Somatic Mutations In The Zinc Transporter ZnT1 Cause Primary Aldosteronism

Disclosure: J. Rege: None. S. Bandulik: None. K. Nanba: None. C. Kosmann: None. A. Blinder: None. A. Plain: None. P. Vats: None. C. Kumar-Sinha: None. A.M. Lerario: None. T. Else: None. Y. Yamazaki: None. F. Satoh: None. H. Sasano: None. T.J. Giordano: None. T.A. Williams: None. M. Reincke: None. A. Turcu: None. A. Udager: None. R. Warth: None. W.E. Rainey: None. Primary aldosteronism (PA) is the most common form of endocrine hypertension and affects approximately one in 50 adults. PA is characterized by inappropriately elevated adrenal aldosterone production via renin-independent mechanisms. Aldosterone-driver somatic mutations in a G protein-coupled inwardly rectifying potassium channel (KCNJ5), Na(+)/K(+) and Ca(2+) ATPases (ATP1A1 and ATP2B3, respectively), L-type and T-type voltage-gated calcium channels (CACNA1D and CACNA1H, respectively), and chloride voltage-gated channel (CLCN2) have been found in approximately 90% of adrenal aldosterone-producing adenomas (APAs). Other causes of lateralized adrenal PA include aldosterone-producing nodules (APNs). Using next-generation sequencing, we identified recurrent in-frame deletions in SLC30A1 in four APAs and one APN (p.L51_A57del, n=3; p.L49_L55del, n=2). SLC30A1 encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). The identified SLC30A1 variants are situated in close proximity to the zinc-binding site (His43 and Asp47) in transmembrane domain II and likely cause abnormal ion transport. PA cases with the unique SLC30A1 mutations showed male dominance and demonstrated increased serum aldosterone and 18-oxo-cortisol concentrations. Functional studies of the mutant SLC30A1(51_57del) variant in a doxycycline-inducible adrenal cell system revealed pathologic Na(+) influx caused by the mutant. Aberrant Na(+) current led to the depolarization of the resting membrane potential, and thus to the opening of voltage-gated calcium channels. This resulted in an increase in cytosolic Ca(2+) activity, which stimulated CYP11B2 mRNA expression and aldosterone production. Collectively, these data implicate the first-in-field zinc transporter mutations as a dominant driver of aldosterone excess in PA. Presentation: Thursday, June 15, 2023