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...

Full description

Saved in:

Bibliographic Details
Published in:	eLife Vol. 4; p. e06315
Main Authors:	Scholl, Ute I, 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
Format:	Journal Article
Language:	English
Published:	England eLife Sciences Publications Ltd 24-04-2015 eLife Sciences Publications, Ltd
Subjects:	Adolescent adrenal gland Adrenal glands Adult Age Age of Onset Aldosterone Aldosterone - biosynthesis Aldosterone - secretion Amino Acid Sequence Calcium (intracellular) Calcium - metabolism Calcium channels (voltage-gated) Calcium Channels, T-Type - genetics Calcium Channels, T-Type - metabolism Calcium Signaling Calcium signalling CaV3.2 Child Child, Preschool Children Consortia de novo mutation Endocrine disorders exome sequencing Female Gene Expression Genes Genes and Chromosomes Genomes Genomics Genotype Haplotypes Heterozygote Human Biology and Medicine Humans Hyperaldosteronism - complications Hyperaldosteronism - genetics Hyperaldosteronism - metabolism Hyperaldosteronism - pathology Hypertension Hypertension - complications Hypertension - genetics Hypertension - metabolism Hypertension - pathology incomplete penetrance Infant Male Medicin och hälsovetenskap Membrane Potentials Middle Aged Molecular Sequence Data Morbidity Mutation Nephrology Pathology Pediatrics Phenotype Recurrence Sequence Alignment Statistical analysis voltage-gated calcium channel Zona Glomerulosa - metabolism Zona Glomerulosa - pathology United States > US human biology incomplete penetrance de novo mutation voltage-gated calcium channel exome sequencing genes chromosomes adrenal gland medicine CaV3.2 human
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.06315