Session: SAT-LB-Late-Breaking Poster Session 1
Bench to Bedside
Poster Board SAT-LB-06
Exome sequencing showed nine of the 10 APAs to have a novel somatic mutation in one or other of two genes which encode either a Na+,K+-ATPase (n=4) or voltage-dependent Ca2+ channel (Cav) subunit (n=5). Two of the mutations occurred twice in the 10 samples, including the L104R mutation of ATP1A1 discovered independently, and replicated in 7/199 unselected APAs (2). This, and a 100-104del mutation spanning the same L104 residue, not only blocked Na+,K+ transport but caused a large inward leak of Na+ and H+ in oocytes; ATP1A1 L104R caused a 2-3 fold increase in aldosterone secretion and CYP11B2 expression in human adrenocortical cells. 5/39 APAs in a Czech cohort diagnosed in some cases by adrenal vein sampling (AVS) alone (i.e. with normal adrenal CT), had the L104R (n=4) or Cav mutations, compared to only 2/50 patients in a less selected Dutch cohort, and 0/42 of the controls. The function of the Cav mutations is not yet certain; but their clustering, conserved positions and recurrence in further APAs support a causal role. All APAs with the novel Na+,K+-ATPase or Cav mutations were <2 cms in diameter (eight were < 1cm), and had >40% compact cells. Unsupervised cluster analysis of the microarray data separated KCNJ5 mutant APAs from those with the new mutations; qPCR confirmed a cluster of genes which were more highly expressed both in normal ZG than ZF, and in APAs with the new mutations than the KCNJ5 mutants. IHC showed the Na+,K+-ATPase and Cavproteins themselves to be more abundant in ZG than ZF, and in the APAs of ZG-like phenotype.
The Na+,K+-ATPase and Cav mutations appear to define a subtype of APA, probably arising in ZG. The small size of the APAs (due partly to the more compact cells) and their higher prevalence in cohorts where absence of adenoma on CT or MRI did not preclude further investigation, suggest that ZG-like APAs are an easily overlooked, potentially curable cause of hypertension.
Nothing to Disclose: EAA, HP, JZ, MC, CM, EB, WZ, LH, CB, TD, BT, APD, BK, JC, GY, IM, MS, JD, ISF, PN, MJB
*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm