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

Ute I Scholl ,Majid Rasoulpour,Britney G Frazier,Erin Loring,Gerald Goh,Tobias Carling,Gabriel Stölting,Ivo Quack,Anne Thiel,Howard Trachtman,Murim Choi,David L Bowlin,Christoph Fahlke,Lars Christian Rump ,Manju L Prasad ,Carol Nelson‐Williams ,Christine B Sethna ,Marc B Lande ,Alfred A Vichot ,C Christofer Juhlin ,Richard P Lifton

doi:10.7554/elife.06315

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.

Highlights

The steroid hormone aldosterone is normally produced in the adrenal zona glomerulosa in response to either angiotensin II, which is produced in response to volume depletion, or hyperkalemia
From a cohort of more than 1500 unrelated subjects referred for evaluation of genetic forms of hypertension, we identified 40 subjects diagnosed with hypertension and primary aldosteronism (PA) by age 10 years in whom disease-causing mutations in CYP11B2, KCNJ5, and CACNA1D (Lifton et al, 1992; Choi et al, 2011; Scholl et al, 2013) were excluded
The effects of this mutation phenocopy the adrenal effects of PA-causing mutations in KCNJ5 (Choi et al, 2011) and CACNA1D (Scholl et al, 2013), demonstrating a shared final common pathway by which PA results from increased Ca2+ entry via voltage-gated channels

Summary

Introduction

The steroid hormone aldosterone is normally produced in the adrenal zona glomerulosa in response to either angiotensin II, which is produced in response to volume depletion, or hyperkalemia (high plasma K+ level). Both stimuli cause membrane depolarization, activating voltage-gated Ca2+ channels; Scholl et al eLife 2015;4:e06315. Most mutations that are currently known were discovered by tracing their effects through families. This allows the locations of mutations to be pinpointed on chromosomes—the structures that genetic material is packaged into. A trait may appear sporadically in a family because the mutation arises anew in the affected subject

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Conclusion