Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism.
Elife
; 4: e06315, 2015 Apr 24.
Article
en En
| MEDLINE
| ID: mdl-25907736
ABSTRACT
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 CACNA1H(M1549V) 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. CACNA1H(M1549V) showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca(2+), the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Calcio
/
Canales de Calcio Tipo T
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Hiperaldosteronismo
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Hipertensión
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Mutación
Tipo de estudio:
Etiology_studies
Idioma:
En
Revista:
Elife
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos