title: Clinical and Steroidogenic Characteristics of Aldosterone-Producing Adenomas With ATPase or CACNA1D Gene Mutations.
abstract: OBJECTIVE
  This comparative study clarified the clinical characteristics and in vitro steroidogenic activities of aldosterone-producing adenomas (APAs) harboring ATPase or CACNA1D gene mutations.
  
  
  METHODS
  Genetic testing was performed on 159 unilateral APAs. Somatic ATPase and CACNA1D gene mutations were analyzed in 42 APA tissues without KCNJ5 gene mutations.
  
  
  RESULTS
  ATP1A1, ATP2B3, and CACNA1D mutations were detected in one, four, and four patients, respectively. Compared with patients without KCNJ5, ATPase, or CACNA1D mutations (wild type), ATPase mutations tended to have more severe hyperaldosteronism and smaller tumors; those with CACNA1D mutations had clinical characteristics and tumor sizes similar to those with wild-type genes. APAs with ATPase mutations were composed mainly of compact eosinophilic tumor cells, whereas CACNA1D mutations resulted in predominantly clear tumor cells. Aldosterone production in APA cells with ATP2B3 mutations were more responsive to dibutyryl cAMP, whereas those with CACNA1D mutations were more responsive to adrenocorticotropic hormone than the wild-type cells.
  
  
  CONCLUSIONS
  APAs with ATPase mutations demonstrated a potentially severe primary aldosteronism phenotype, whereas those with CACNA1D mutations displayed characteristics similar to wild-type APAs. The status of stimulated aldosterone production was also different according to the cell types, suggesting that the regulatory effects of adrenocorticotropic hormone on aldosterone synthesis could possibly vary according to the intracellular signaling involved in hormone production.
authors.affiliation: Endocrinology and Diabetes Center (T.K., S.S., Y.M., J.S., M.O., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; and Department of Pathology (Y.Y., Y.N., H.S.), Tohoku University School of Medicine, Sendai 980-8575, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kitamoto
authors.affiliation: Endocrinology and Diabetes Center (T.K., S.S., Y.M., J.S., M.O., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; and Department of Pathology (Y.Y., Y.N., H.S.), Tohoku University School of Medicine, Sendai 980-8575, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Suematsu
authors.affiliation: Endocrinology and Diabetes Center (T.K., S.S., Y.M., J.S., M.O., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; and Department of Pathology (Y.Y., Y.N., H.S.), Tohoku University School of Medicine, Sendai 980-8575, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Endocrinology and Diabetes Center (T.K., S.S., Y.M., J.S., M.O., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; and Department of Pathology (Y.Y., Y.N., H.S.), Tohoku University School of Medicine, Sendai 980-8575, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Endocrinology and Diabetes Center (T.K., S.S., Y.M., J.S., M.O., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; and Department of Pathology (Y.Y., Y.N., H.S.), Tohoku University School of Medicine, Sendai 980-8575, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
authors.affiliation: Endocrinology and Diabetes Center (T.K., S.S., Y.M., J.S., M.O., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; and Department of Pathology (Y.Y., Y.N., H.S.), Tohoku University School of Medicine, Sendai 980-8575, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Matsuzawa
authors.affiliation: Endocrinology and Diabetes Center (T.K., S.S., Y.M., J.S., M.O., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; and Department of Pathology (Y.Y., Y.N., H.S.), Tohoku University School of Medicine, Sendai 980-8575, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Saito
authors.affiliation: Endocrinology and Diabetes Center (T.K., S.S., Y.M., J.S., M.O., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; and Department of Pathology (Y.Y., Y.N., H.S.), Tohoku University School of Medicine, Sendai 980-8575, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Omura
authors.affiliation: Endocrinology and Diabetes Center (T.K., S.S., Y.M., J.S., M.O., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; and Department of Pathology (Y.Y., Y.N., H.S.), Tohoku University School of Medicine, Sendai 980-8575, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nishikawa
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis*; D003994:Bucladesine / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006929:Hyperaldosteronism / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000096:biosynthesis / Q000235:genetics; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics; D012083:Renin / Q000097:blood; D012189:Retrospective Studies; D013256:Steroids / Q000096:biosynthesis*
chemical_list: C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D044103:Receptor, Melanocortin, Type 2; D013256:Steroids; D000450:Aldosterone; D003994:Bucladesine; D000324:Adrenocorticotropic Hormone; D012083:Renin; D000251:Adenosine Triphosphatases; D053499:Plasma Membrane Calcium-Transporting ATPases; C506962:ATP2B3 protein, human; D006854:Hydrocortisone