title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
abstract: Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca(2+) influx cause ∼40% of these tumors. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca(2+) channel mutations in APAs and primary aldosteronism.
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Ute I
authors.initials: UI
authors.lastname: Scholl
authors.forename: Gerald
authors.initials: G
authors.lastname: Goh
authors.forename: Gabriel
authors.initials: G
authors.lastname: Stölting
authors.forename: Regina Campos
authors.initials: RC
authors.lastname: de Oliveira
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.forename: John D
authors.initials: JD
authors.lastname: Overton
authors.forename: Annabelle L
authors.initials: AL
authors.lastname: Fonseca
authors.forename: Reju
authors.initials: R
authors.lastname: Korah
authors.forename: Lee F
authors.initials: LF
authors.lastname: Starker
authors.forename: John W
authors.initials: JW
authors.lastname: Kunstman
authors.forename: Manju L
authors.initials: ML
authors.lastname: Prasad
authors.forename: Erum A
authors.initials: EA
authors.lastname: Hartung
authors.forename: Nelly
authors.initials: N
authors.lastname: Mauras
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Benson
authors.forename: Tammy
authors.initials: T
authors.lastname: Brady
authors.forename: Jay R
authors.initials: JR
authors.lastname: Shapiro
authors.forename: Erin
authors.initials: E
authors.lastname: Loring
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.forename: Steven K
authors.initials: SK
authors.lastname: Libutti
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.forename: Per
authors.initials: P
authors.lastname: Hellman
authors.forename: Gunnar
authors.initials: G
authors.lastname: Westin
authors.forename: Göran
authors.initials: G
authors.lastname: Åkerström
authors.forename: Peyman
authors.initials: P
authors.lastname: Björklund
authors.forename: Tobias
authors.initials: T
authors.lastname: Carling
authors.forename: Christoph
authors.initials: C
authors.lastname: Fahlke
authors.forename: Patricia
authors.initials: P
authors.lastname: Hidalgo
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism; D018246:Adrenocortical Adenoma / Q000235:genetics* / Q000378:metabolism; D000450:Aldosterone / Q000096:biosynthesis; D000595:Amino Acid Sequence; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011487:Protein Conformation; D016415:Sequence Alignment
chemical_list: C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type; D000450:Aldosterone
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