A Mutation in the KCNE3 Potassium Channel Gene Is Associated with Susceptibility to Thyrotoxic Hypokalemic Periodic Paralysis

TLDR

Hypokalemic Periodic Paralyses are acute, reversible muscle weakness disorders caused by low potassium, with the most common forms being autosomal dominant familial and thyrotoxic‑associated types, the latter distinguished by thyrotoxicosis and linked to mutations in ion‑channel genes such as KCNE3. The study aimed to determine whether thyrotoxic hypokalemic periodic paralysis shares the same ion‑channel mutations as familial hypokalemic periodic paralysis, implying a genetic predisposition. The authors screened 15 THypoKPP patients with target‑exon PCR, CSGE, and sequencing to rule out CACN1AS and SCN4A mutations. They identified the R83H mutation in KCNE3 in a sporadic THypoKPP patient and in two of three relatives, establishing KCNE3 as the first genetic defect linked to thyrotoxic hypokalemic periodic paralysis.

Abstract

Abstract Hypokalemic Periodic Paralyses comprise diverse diseases characterized by acute and reversible attacks of severe muscle weakness, associated with low serum potassium. The most common causes are Familial Hypokalemic Periodic Paralysis (FHypoKPP), an autosomal dominant disease, and Thyrotoxic Hypokalemic Periodic Paralysis (THypoKPP), secondary to thyrotoxicosis. Symptoms of paralysis are similar in both diseases, distinguished by thyrotoxicosis present in THypoKPP. FHypoKPP is caused by mutations in ionic channel genes calcium (CACN1AS), sodium (SCN4A) and potassium (KCNE3). Since both diseases are similar, we tested the hypothesis that THypoKPP could carry the same mutations described in FHypoKPP, being the paralysis a genetically conditioned complication of thyrotoxicosis. In 15 patients with THypoKPP, using target-exon PCR, CSGE screening, and direct sequencing, we excluded known mutations in CACN1AS and SCN4A genes. On the other hand, we were able to identify the R83H mutation in the KCNE3 gene in one sporadic case of THypoKPP, a man who had been asymptomatic until developing thyrotoxicosis caused by Graves’ disease; we confirmed the disease-causing mutation in 2 of 3 descendants. R83H was recently found in two FHypoKPP unrelated families, in which the mutant decreased outward potassium flux, resulting in a more positive resting membrane potential. We, therefore, identified the first genetic defect in THypoKPP, a mutation in the KCNE3 gene.