title: Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension.
abstract: At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were reported to occur in APAs. We find that KCNJ5 mutations are common in APAs resembling cortisol-secreting cells of the adrenal zona fasciculata but are absent in a subset of APAs resembling the aldosterone-secreting cells of the adrenal zona glomerulosa. We performed exome sequencing of ten zona glomerulosa-like APAs and identified nine with somatic mutations in either ATP1A1, encoding the Na(+)/K(+) ATPase α1 subunit, or CACNA1D, encoding Cav1.3. The ATP1A1 mutations all caused inward leak currents under physiological conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Many APAs with these mutations were <1 cm in diameter and had been overlooked on conventional adrenal imaging. Recognition of the distinct genotype and phenotype for this subset of APAs could facilitate diagnosis.
authors.affiliation: Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Elena A B
authors.initials: EA
authors.lastname: Azizan
authors.forename: Hanne
authors.initials: H
authors.lastname: Poulsen
authors.forename: Petronel
authors.initials: P
authors.lastname: Tuluc
authors.forename: Junhua
authors.initials: J
authors.lastname: Zhou
authors.forename: Michael V
authors.initials: MV
authors.lastname: Clausen
authors.forename: Andreas
authors.initials: A
authors.lastname: Lieb
authors.forename: Carmela
authors.initials: C
authors.lastname: Maniero
authors.forename: Sumedha
authors.initials: S
authors.lastname: Garg
authors.forename: Elena G
authors.initials: EG
authors.lastname: Bochukova
authors.forename: Wanfeng
authors.initials: W
authors.lastname: Zhao
authors.forename: Lalarukh Haris
authors.initials: LH
authors.lastname: Shaikh
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Brighton
authors.forename: Ada E D
authors.initials: AE
authors.lastname: Teo
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davenport
authors.forename: Tanja
authors.initials: T
authors.lastname: Dekkers
authors.forename: Bas
authors.initials: B
authors.lastname: Tops
authors.forename: Benno
authors.initials: B
authors.lastname: Küsters
authors.forename: Jiri
authors.initials: J
authors.lastname: Ceral
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
authors.forename: Sudeshna Guha
authors.initials: SG
authors.lastname: Neogi
authors.forename: Ian
authors.initials: I
authors.lastname: McFarlane
authors.forename: Nitzan
authors.initials: N
authors.lastname: Rosenfeld
authors.forename: Francesco
authors.initials: F
authors.lastname: Marass
authors.forename: James
authors.initials: J
authors.lastname: Hadfield
authors.forename: Wojciech
authors.initials: W
authors.lastname: Margas
authors.forename: Kanchan
authors.initials: K
authors.lastname: Chaggar
authors.forename: Miroslav
authors.initials: M
authors.lastname: Solar
authors.forename: Jaap
authors.initials: J
authors.lastname: Deinum
authors.forename: Annette C
authors.initials: AC
authors.lastname: Dolphin
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Joerg
authors.initials: J
authors.lastname: Striessnig
authors.forename: Poul
authors.initials: P
authors.lastname: Nissen
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Brown
mesh_terms: D000303:Adrenal Cortex Diseases / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D019943:Amino Acid Substitution; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D008297:Male; D009154:Mutation; D011487:Protein Conformation; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; C499076:ATP1A1 protein, human; D000254:Sodium-Potassium-Exchanging ATPase
references.citation: J Neurosci. 2005 Jan 5;25(1):252-9
references.pmid: 15634789
references.citation: Endocrinology. 2005 Jun;146(6):2650-6
references.pmid: 15731365
references.citation: Science. 2011 Feb 11;331(6018):768-72
references.pmid: 21311022
references.citation: Endocrinology. 1978 Dec;103(6):1997-2005
references.pmid: 218796
references.citation: J Clin Endocrinol Metab. 1996 Nov;81(11):4129-36
references.pmid: 8923871
references.citation: J Clin Endocrinol Metab. 2010 May;95(5):2296-305
references.pmid: 20200334
references.citation: Endocr Pathol. 2009 Spring;20(1):66-72
references.pmid: 19199080
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8089-96; discussion 8086-8
references.pmid: 15863612
references.citation: J Clin Endocrinol Metab. 2012 May;97(5):E819-29
references.pmid: 22442279
references.citation: Nature. 2013 Mar 14;495(7440):260-4
references.pmid: 23455422
references.citation: Postgrad Med J. 1999 Apr;75(882):235-6
references.pmid: 10715768
references.citation: J Membr Biol. 2004 Mar 15;198(2):65-76
references.pmid: 15138746
references.citation: Proc Natl Acad Sci U S A. 2005 May 24;102(21):7553-8
references.pmid: 15897456
references.citation: J Biol Chem. 2001 Jun 22;276(25):22100-6
references.pmid: 11285265
references.citation: Peptides. 2004 Aug;25(8):1269-77
references.pmid: 15350694
references.citation: Nat Neurosci. 2011 Jan;14(1):77-84
references.pmid: 21131953
references.citation: Nature. 2013 Mar 14;495(7440):265-9
references.pmid: 23455424
references.citation: Nat Neurosci. 2006 Sep;9(9):1108-16
references.pmid: 16921373
references.citation: Hypertension. 2012 Mar;59(3):537-8
references.pmid: 22275537
references.citation: Cell Biol Int. 1993 Dec;17(12):1107-16
references.pmid: 8118453
references.citation: J Am Coll Cardiol. 2006 Dec 5;48(11):2293-300
references.pmid: 17161262
references.citation: J Clin Endocrinol Metab. 2012 Jan;97(1):100-9
references.pmid: 22112805
references.citation: Metabolism. 1999 Sep;48(9):1167-71
references.pmid: 10484059
references.citation: Nat Rev Endocrinol. 2011 May 24;7(8):485-95
references.pmid: 21610687
references.citation: J Cell Physiol. 2005 Dec;205(3):393-401
references.pmid: 15887230
references.citation: Endocrinology. 1969 Apr;84(4):808-13
references.pmid: 5766540
references.citation: Nature. 2007 Dec 13;450(7172):1043-9
references.pmid: 18075585
references.citation: Hypertension. 2012 Mar;59(3):592-8
references.pmid: 22275527
references.citation: Nat Genet. 2013 Apr;45(4):440-4, 444e1-2
references.pmid: 23416519
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12706-11
references.pmid: 16123128
references.citation: Nature. 2010 Sep 2;467(7311):99-102
references.pmid: 20720542