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Chloride Ion Channel Mutations Implicated in Hormone Condition Leading to Hypertension

NEW YORK (GenomeWeb) – Two research teams have identified genetic factors contributing to a hormonal condition called aldosteronism — excess production of the adrenal gland hormone aldosterone — that can lead to severe secondary arterial hypertension.

For one of the studies, both published today in Nature Genetics, researchers from Germany, the US, Korea, and Australia did Illumina exome sequencing on a multigenerational family that was particularly prone to type II familial hyperaldosteronism. After narrowing in on heterozygous variants affecting the chromosome 3 voltage-gated chloride channel-coding gene CLCN2 in affected individuals that were missing in unrelated, hyperaldosteronism-free individuals, they did targeted Sanger sequencing on dozens more individuals with early-onset primary aldosteronism.

The team narrowed in on heterozygous CLCN2 variants another eight affected individuals, including two de novo mutations and four cases marked by the same substitution mutation found in the first family profiled. Together with cell line experiments, the sequence pointed to ties between hyperaldosteronism and CLCN2 chloride channel mutations that boost adrenal gland glomerulosa cell membrane depolarization and subsequent aldosterone production.

"These findings for the first time demonstrate a role of anion channels in glomerulosa membrane potential determination, aldosterone production, and hypertension," senior author Richard Lifton, a human genetics and genomics researcher affiliated with Yale University and the Rockefeller University, and his colleagues wrote. "They establish the cause of a substantial fraction of early-onset primary aldosteronism."

That team noted that prior studies on idiopathic forms of hyperaldosteronism have led to suspicious somatic or germline mutations in genes contributing to aldosterone biosynthesis pathway, which appears to occur as a consequence of voltage-gated calcium ion channel activation following depolarization of the glomerulosa cell membrane.

Based on their data, Lifton and his colleagues estimated that rare mutations in CLCN2 account for some 10 percent of early-onset aldosteronism cases, prompting them to suggest that "[g]enetic testing for germline mutations in CLCN2 and other genes involved in early primary aldosteronism can be useful for establishing diagnosis, defining treatment options, and assessing risk to future offspring.

In another Nature Genetics study, an international team led by investigators in France and Germany also uncovered associations between at least one CLCN2 mutation and primary aldosteronism by performing exome sequencing on a dozen individuals with early-onset forms of hyperaldosteronism and hypertension.

Starting from a family with affected and unaffected siblings, the researchers found a de novo germline mutation that was heterozygous in the affected child — who was diagnosed with hyperaldosteronism when she was nine years old — but absent in sequences from her unaffected parents, her sibling, and from available population sequence databases.

The team did not see other worrisome mutations in the CLCN2 sequences from 11 more individuals with hyperaldosteronism who were assessed by exome sequencing for that study.

But when they used patch clamp electrophysiology experiments to follow ion currents in Xenopus laevis egg cells expressing the version of CLCN2 found in the index case, the researchers saw enhanced ion channel activity that seemed to stem from gain-of-function changes to a CLCN2 region normally tasked with keeping excess depolarization in check unless appropriate voltage and/or timing signals are present.

Such results were further supported by the expression patterns the authors detected in human adrenocortical cell line with or without this CLCN2 mutation, prompting them to propose that "the increased [chloride ion] currents may overcome the hyper-polarizing currents of [potassium ion] channels that normally determine the glomerulosa cell resting potential." 

Co-corresponding authors Maria-Christina Zennaro, a cardiovascular researcher affiliated with INSERM and Paris Descartes University, and Thomas Jentsch, with the Leibniz Research Institute for Molecular Pharmacology and the Max Delbrück Center for Molecular Medicine, and their colleagues further explained, "The inhibition of these potassium channels …  are the main mechanisms triggering aldosterone production under physiological conditions … The discovery that a chloride channel is involved in primary aldosteronism opens new and unexpected perspectives for the pathogenesis and treatment of arterial hypertension." 

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