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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1050-1054 |
| Number of pages | 5 |
| Journal | Nature Genetics |
| Volume | 45 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2013 |
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ASJC Scopus subject areas
- Genetics
- Medicine(all)
Cite this
Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. / Scholl, Ute I.; Goh, Gerald; Stölting, Gabriel; De Oliveira, Regina Campos; Choi, Murim; Overton, John D.; Fonseca, Annabelle L.; Korah, Reju; Starker, Lee F.; Kunstman, John W.; Prasad, Manju L.; Hartung, Erum A.; Mauras, Nelly; Benson, Matthew R.; Brady, Tammy; Shapiro, Jay R.; Loring, Erin; Nelson-Williams, Carol; Libutti, Steven K.; Mane, Shrikant; Hellman, Per; Westin, Gunnar; Åkerström, Göran; Björklund, Peyman; Carling, Tobias; Fahlke, Christoph; Hidalgo, Patricia; Lifton, Richard P.
In: Nature Genetics, Vol. 45, No. 9, 09.2013, p. 1050-1054.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism
AU - Scholl, Ute I.
AU - Goh, Gerald
AU - Stölting, Gabriel
AU - De Oliveira, Regina Campos
AU - Choi, Murim
AU - Overton, John D.
AU - Fonseca, Annabelle L.
AU - Korah, Reju
AU - Starker, Lee F.
AU - Kunstman, John W.
AU - Prasad, Manju L.
AU - Hartung, Erum A.
AU - Mauras, Nelly
AU - Benson, Matthew R.
AU - Brady, Tammy
AU - Shapiro, Jay R.
AU - Loring, Erin
AU - Nelson-Williams, Carol
AU - Libutti, Steven K.
AU - Mane, Shrikant
AU - Hellman, Per
AU - Westin, Gunnar
AU - Åkerström, Göran
AU - Björklund, Peyman
AU - Carling, Tobias
AU - Fahlke, Christoph
AU - Hidalgo, Patricia
AU - Lifton, Richard P.
PY - 2013/9
Y1 - 2013/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84883464824&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883464824&partnerID=8YFLogxK
U2 - 10.1038/ng.2695
DO - 10.1038/ng.2695
M3 - Article
C2 - 23913001
AN - SCOPUS:84883464824
VL - 45
SP - 1050
EP - 1054
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 9
ER -