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

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          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 (Ca V3.2) 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.

          DOI: http://dx.doi.org/10.7554/eLife.06315.001

          eLife digest

          The consequence of mutations to the large majority of human genes is unknown. 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. Other mutations are harder to trace because individuals with these mutations may develop very different signs and symptoms, or not develop clinical abnormalities at all. Alternatively, a trait may appear sporadically in a family because the mutation arises anew in the affected subject.

          Recently developed technologies that allow scientists to rapidly sequence all the gene-encoding regions of an individual's DNA—their genome—offer a new way to identify harmful genetic variants. Comparing the genomes of individuals with rare disorders can reveal if the individuals share any genetic mutations in common that could cause their symptoms.

          Scholl et al. used this strategy to sequence the genomes of 40 individuals with a rare type of hypertension—a condition that causes high blood pressure, and increases the risk of strokes, kidney failure and heart attacks—that develops early in childhood. In this form of the disease, high blood pressure is caused by the adrenal glands above the kidneys producing too much of a hormone called aldosterone. Some genetic causes of this form of the disease have already been identified. Now, Scholl et al. have found a new genetic mutation present in five families with this condition. Two of the individuals were the first in their families to develop this mutation, while three others inherited it. Some of the family members with this mutation had hypertension and some did not.

          The mutation is in a gene that encodes a type of calcium channel—a protein found in the membrane that surrounds cells, and which can open and close to control the amount of calcium in the cell. This particular calcium channel is abundant in the cells of the adrenal gland. Scholl et al. found that the mutation causes the calcium channels to be more likely to open and take longer to close. This increases the number of calcium ions that move into the cell, which causes the adrenal gland to produce more aldosterone. These new insights have provided a new way of diagnosing early-onset hypertension, and suggest that targeting calcium channels could help to develop new treatments for this disease.

          DOI: http://dx.doi.org/10.7554/eLife.06315.002

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          Most cited references 45

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          Molecular physiology of low-voltage-activated t-type calcium channels.

          T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the alpha1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.
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            A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients.

            We prospectively investigated the prevalence of curable forms of primary aldosteronism (PA) in newly diagnosed hypertensive patients. The prevalence of curable forms of PA is currently unknown, although retrospective data suggest that it is not as low as commonly perceived. Consecutive hypertensive patients referred to 14 hypertension centers underwent a diagnostic protocol composed of measurement of Na+ and K+ in serum and 24-h urine, sitting plasma renin activity, and aldosterone at baseline and after 50 mg captopril. The patients with an aldosterone/renin ratio >40 at baseline, and/or >30 after captopril, and/or a probability of PA (by a logistic discriminant function) > or =50% underwent imaging tests and adrenal vein sampling (AVS) or adrenocortical scintigraphy to identify the underlying adrenal pathology. An aldosterone-producing adenoma (APA) was diagnosed in patients who in addition to excess autonomous aldosterone secretion showed: 1) lateralized aldosterone secretion at AVS or adrenocortical scintigraphy, 2) adenoma at surgery and pathology, and 3) a blood pressure decrease after adrenalectomy. Evidence of excess autonomous aldosterone secretion without such criteria led to a diagnosis of idiopathic hyperaldosteronism (IHA). A total of 1,180 patients (age 46 +/- 12 years) were enrolled; a conclusive diagnosis was attained in 1,125 (95.3%). Of these, 54 (4.8%) had an APA and 72 (6.4%) had an IHA. There were more APA (62.5%) and fewer IHA cases (37.5%) at centers where AVS was available (p = 0.002); the opposite occurred where AVS was unavailable. In newly diagnosed hypertensive patients referred to hypertension centers, the prevalence of APA is high (4.8%). The availability of AVS is essential for an accurate identification of the adrenocortical pathologies underlying PA.
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              Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline.

              Our objective was to develop clinical practice guidelines for the diagnosis and treatment of patients with primary aldosteronism. The Task Force comprised a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, six additional experts, one methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. Systematic reviews of available evidence were used to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group criteria to describe both the quality of evidence and the strength of recommendations. We used "recommend" for strong recommendations and "suggest" for weak recommendations. Consensus was guided by systematic reviews of evidence and discussions during one group meeting, several conference calls, and multiple e-mail communications. The drafts prepared by the task force with the help of a medical writer were reviewed successively by The Endocrine Society's CGS, Clinical Affairs Core Committee (CACC), and Council. The version approved by the CGS and CACC was placed on The Endocrine Society's Web site for comments by members. At each stage of review, the Task Force received written comments and incorporated needed changes. We recommend case detection of primary aldosteronism be sought in higher risk groups of hypertensive patients and those with hypokalemia by determining the aldosterone-renin ratio under standard conditions and that the condition be confirmed/excluded by one of four commonly used confirmatory tests. We recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. We recommend the presence of a unilateral form of primary aldosteronism should be established/excluded by bilateral adrenal venous sampling by an experienced radiologist and, where present, optimally treated by laparoscopic adrenalectomy. We recommend that patients with bilateral adrenal hyperplasia, or those unsuitable for surgery, optimally be treated medically by mineralocorticoid receptor antagonists.

                Author and article information

                Role: Reviewing editor
                eLife Sciences Publications, Ltd
                24 April 2015
                : 4
                [1 ]deptDepartment of Genetics , Howard Hughes Medical Institute, Yale University School of Medicine , New Haven, United States
                [2 ]deptDivision of Nephrology , Heinrich Heine University Düsseldorf , Düsseldorf, Germany
                [3 ]deptInstitute of Complex Systems, Zelluläre Biophysik , Forschungszentrum Jülich , Jülich, Germany
                [4 ]Yale Center for Mendelian Genomics , New Haven, United States
                [5 ]deptDepartment of Pathology , Yale University School of Medicine , New Haven, United States
                [6 ]deptYale Endocrine Neoplasia Laboratory , Yale School of Medicine , New Haven, United States
                [7 ]deptDepartment of Oncology-Pathology, Karolinska Institutet , Karolinska University Hospital , Stockholm, Sweden
                [8 ]deptDivision of Pediatric Nephrology , University of Rochester Medical Center , Rochester, United States
                [9 ]Madigan Army Medical Center , Tacoma, United States
                [10 ]Connecticut Children's Medical Center , Hartford, United States
                [11 ]Intermed Consultants Ltd , Edina, United States
                [12 ]deptDepartment of Pediatrics , Cohen Children's Medical Center of New York , New Hyde Park, United States
                [13 ]deptDepartment of Pediatrics , NYU Langone Medical Center , New York, United States
                Howard Hughes Medical Institute, University of Michigan , United States
                Howard Hughes Medical Institute, University of Michigan , United States
                Author notes
                [* ]For correspondence: richard.lifton@ 123456yale.edu
                © 2015, Scholl et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                Funded by: FundRef http://dx.doi.org/10.13039/100000002, universityNational Institutes of Health (NIH);
                Award ID: Centers for Mendelian Genomics, 5U54HG006504
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000011, universityHoward Hughes Medical Institute (HHMI);
                Award ID: Investigator Program
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001348, Agency for Science, Technology and Research (A*STAR);
                Award ID: Scholarship
                Award Recipient :
                Funded by: Ministry of Innovation, Science, Research and Technology of the state of North Rhine-Westphalia;
                Award ID: Rückkehrerprogramm
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Research Article
                Genes and Chromosomes
                Human Biology and Medicine
                Custom metadata
                A novel Mendelian disease featuring early-onset hypertension is caused by a recurrent gain of function mutation in CACNA1H, which encodes the voltage-gated calcium channel Cav3.2.


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