title: A mutation in the KCNE3 potassium channel gene is associated with susceptibility to thyrotoxic hypokalemic periodic paralysis.
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.
authors.affiliation: Laboratory of Molecular Endocrinology, Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo 781, 04039-032 São Paulo, SP, Brazil.
authors.forename: Magnus R
authors.initials: MR
authors.lastname: Dias Da Silva
authors.forename: Janete M
authors.initials: JM
authors.lastname: Cerutti
authors.forename: Liliane A T
authors.initials: LA
authors.lastname: Arnaldi
authors.forename: Rui M B
authors.initials: RM
authors.lastname: Maciel
mesh_terms: D000328:Adult; D013956:Antithyroid Agents / Q000627:therapeutic use; D020022:Genetic Predisposition to Disease; D006801:Humans; D020514:Hypokalemic Periodic Paralysis / Q000188:drug therapy / Q000235:genetics*; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008297:Male; D008564:Membrane Potentials; D008713:Methimazole / Q000627:therapeutic use; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D011189:Potassium Chloride / Q000627:therapeutic use; D013971:Thyrotoxicosis / Q000150:complications* / Q000235:genetics* / Q000628:therapy
chemical_list: D013956:Antithyroid Agents; D007457:Iodine Radioisotopes; C418492:KCNE3 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D008713:Methimazole; D011189:Potassium Chloride