Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism.

TitleRecurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism.
Publication TypeJournal Article
Year of Publication2015
AuthorsScholl, UI, Stölting, G, Nelson-Williams, C, Vichot, AA, Choi, M, Loring, E, Prasad, ML, Goh, G, Carling, T, C Juhlin, C, Quack, I, Rump, LC, Thiel, A, Lande, M, Frazier, BG, Rasoulpour, M, Bowlin, DL, Sethna, CB, Trachtman, H, Fahlke, C, Lifton, RP
Date Published2015 Apr 24
KeywordsAdolescent, Adult, Age of Onset, Aldosterone, Amino Acid Sequence, Calcium, Calcium Channels, T-Type, Calcium Signaling, Child, Child, Preschool, Female, Gene Expression, Genotype, Heterozygote, Humans, Hyperaldosteronism, Hypertension, Infant, Male, Membrane Potentials, Middle Aged, Molecular Sequence Data, Mutation, Phenotype, Recurrence, Sequence Alignment, Zona Glomerulosa

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.

Alternate JournalElife
PubMed ID25907736
PubMed Central IDPMC4408447
Grant List5U54HG006504 / HG / NHGRI NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
T32 DK007276 / DK / NIDDK NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
UL1 TR000142 / TR / NCATS NIH HHS / United States
P30 CA016359 / CA / NCI NIH HHS / United States
P01 DK017433 / DK / NIDDK NIH HHS / United States