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Endocrine Abstracts (2016) 41 GP7 | DOI: 10.1530/endoabs.41.GP7

1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch, Luxembourg; 2Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany; 3Department of Pharmacology, Saarland University Medical Center, Homburg, Germany; 4Department of Internal Medicine II, Saarland University Medical Center, Homburg, Germany; 5Telefonica Research and Development, Barcelona, Spain; 6Hospital Universitario de Alicante, University Miguel Hernández, Alicante, Spain.

Introduction: Primary aldosteronism (PA) occurs due to an excess production of aldosterone in the adrenal glands, resulting in low renin levels and hypertension. Familial hyperaldosteronism is considered to be a relatively rare disorder, with only a small number of genes having been implicated so far. The aim of the present study is to identify the molecular cause of disease in a PA family, as well as examining the mechanisms in an in vitro setting.

Patients and methods: Comprehensive biochemical and clinical phenotyping, as well as genome-level sequencing was performed in the PA family to identify the molecular cause. HEK293T cells then were transfected with wildtype and mutant expression plasmids to enable the production of electrophysiological recordings. To further investigate the potential physiologic effects of the mutation, we measured cytosolic Ca2+ dynamics by fluorescent live cell imaging in the HEK cells with wildtype and mutanted CACNA1H.

Results: We have identified the new heterozygous germline mutation in CACNA1H (p.G1064R) in the PA family. CACNA1H encodes a voltage-gated Ca2+ channel, which is expressed in the adrenal glomerulosa. The mutation lies in a conserved region in the II–III intracellular linker. Electrophysiological recordings showed no significant differences between the wildtype and mutant. However, the fluorescent live cell imaging experiments showed cell populations of HEK293T cells transformed with the mutant variant with significant decrease in average periods of 10s (P=0.02), i.e. greater global spiking activity, compared to the wildtype variant.

Conclusions: Our analysis has identified a new mutation germline in CACNA1H that confers a decrease in average periods leading to greater spiking activity of the mutant. We postulate that these effects cause an increase in the influx of Ca2+ and that this is the stimulus for increased aldosterone production and cellular proliferation in the adrenal glands.

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