title: Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism.
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.
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors.forename: Ute I
authors.initials: UI
authors.lastname: Scholl
authors.affiliation: Institute of Complex Systems, Zelluläre Biophysik, Forschungszentrum Jülich, Jülich, Germany.
authors.forename: Gabriel
authors.identifier: http://orcid.org/0000-0002-2339-0545
authors.initials: G
authors.lastname: Stölting
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Vichot
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors.forename: Erin
authors.initials: E
authors.lastname: Loring
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, United States.
authors.forename: Manju L
authors.initials: ML
authors.lastname: Prasad
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors.forename: Gerald
authors.initials: G
authors.lastname: Goh
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, United States.
authors.forename: Tobias
authors.initials: T
authors.lastname: Carling
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, United States.
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.affiliation: Division of Nephrology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Quack
authors.affiliation: Division of Nephrology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Lars C
authors.initials: LC
authors.lastname: Rump
authors.affiliation: Division of Nephrology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Thiel
authors.affiliation: Division of Pediatric Nephrology, University of Rochester Medical Center, Rochester, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Lande
authors.affiliation: Madigan Army Medical Center, Tacoma, United States.
authors.forename: Britney G
authors.initials: BG
authors.lastname: Frazier
authors.affiliation: Connecticut Children's Medical Center, Hartford, United States.
authors.forename: Majid
authors.initials: M
authors.lastname: Rasoulpour
authors.affiliation: Intermed Consultants Ltd, Edina, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Bowlin
authors.affiliation: Department of Pediatrics, Cohen Children's Medical Center of New York, New Hyde Park, United States.
authors.forename: Christine B
authors.initials: CB
authors.lastname: Sethna
authors.affiliation: Department of Pediatrics, NYU Langone Medical Center, New York, United States.
authors.forename: Howard
authors.initials: H
authors.lastname: Trachtman
authors.affiliation: Institute of Complex Systems, Zelluläre Biophysik, Forschungszentrum Jülich, Jülich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Fahlke
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000450:Aldosterone / Q000096:biosynthesis / Q000378:metabolism; D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D006929:Hyperaldosteronism / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006973:Hypertension / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007223:Infant; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D012008:Recurrence; D016415:Sequence Alignment; D015384:Zona Glomerulosa / Q000378:metabolism / Q000473:pathology
chemical_list: C479952:CACNA1H protein, human; D020747:Calcium Channels, T-Type; D000450:Aldosterone; D002118:Calcium
keywords: CaV3.2; adrenal gland; chromosomes; de novo mutation; exome sequencing; genes; human; human biology; incomplete penetrance; medicine; voltage-gated calcium channel