This title appears in the Scientific Report :
2015
Please use the identifier:
http://dx.doi.org/10.7554/eLife.06315 in citations.
Please use the identifier: http://hdl.handle.net/2128/8544 in citations.
Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism
Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism
Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promis...
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Personal Name(s): | Scholl, Ute I |
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Stölting, Gabriel / Nelson-Williams, Carol / Vichot, Alfred A / Choi, Murim / Loring, Erin / Prasad, Manju L / Goh, Gerald / Carling, Tobias / Juhlin, C Christofer / Quack, Ivo / Rump, Lars C / Thiel, Anne / Lande, Marc / Frazier, Britney G / Rasoulpour, Majid / Bowlin, David L / Sethna, Christine B / Trachtman, Howard / Fahlke, Christoph / Lifton, Richard P (Corresponding Author) | |
Contributing Institute: |
Zelluläre Biophysik; ICS-4 |
Published in: | eLife, 4 (2015) S. e06315 |
Imprint: |
Cambridge
eLife Sciences Publications
2015
|
PubMed ID: |
25907736 |
DOI: |
10.7554/eLife.06315 |
Document Type: |
Journal Article |
Research Program: |
Functional Macromolecules and Complexes |
Link: |
OpenAccess OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://hdl.handle.net/2128/8544 in citations.
Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1HM1549V mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1HM1549V showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca2+, the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension |