Mutations in Potassium Channel Kir2.6 Cause Susceptibility to Thyrotoxic Hypokalemic Periodic Paralysis

Thyrotoxic hypokalemic periodic paralysis (TPP) is characterized by acute attacks of weakness, hypokalemia, and thyrotoxicosis of various etiologies. These transient attacks resemble those of patients with familial hypokalemic periodic paralysis (hypoKPP) and resolve with treatment of the underlying hyperthyroidism. Because of the phenotypic similarity of these conditions, we hypothesized that TPP might also be a channelopathy. While sequencing candidate genes, we identified a previously unreported gene (not present in human sequence databases) that encodes an inwardly rectifying potassium (Kir) channel, Kir2.6. This channel, nearly identical to Kir2.2, is expressed in skeletal muscle and is transcriptionally regulated by thyroid hormone. Expression of Kir2.6 in mammalian cells revealed normal Kir currents in whole-cell and single-channel recordings. Kir2.6 mutations were present in up to 33% of the unrelated TPP patients in our collection. Some of these mutations clearly alter a variety of Kir2.6 properties, all altering muscle membrane excitability leading to paralysis.Muscular Dystrophy AssociationNational Institutes of HealthCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)INSERMAFMC.B. Day FoundationNINDSUniv Calif San Francisco, Grad Program Neurosci, San Francisco, CA 94158 USAUniv Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USAUniv Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USANatl Inst Neurosci, Ion Channel & Transporter Lab, Singapore 308433, SingaporeUniv Paris 06, INSERM, UMRS 546, F-75013 Paris, FranceGrp Hosp Pitie Salpetriere, AP HP, Ctr Reference Canalopathies Musculaires, F-75013 Paris, FranceUniv Hong Kong, Queen Mary Hosp, Dept Med, Hong Kong, Hong Kong, Peoples R ChinaMahidol Univ, Ramathibodi Hosp, Dept Med, Bangkok 10400, ThailandNatl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 308433, SingaporeNatl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 308433, SingaporeSingapore Gen Hosp, Dept Clin Res, Singapore 169608, SingaporeUniv Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USAUniversidade Federal de São Paulo, Div Endocrinol, Dept Med, BR-04039032 São Paulo, BrazilMassachusetts Gen Hosp, Charlestown, MA 02129 USAUniversidade Federal de São Paulo, Div Endocrinol, Dept Med, BR-04039032 São Paulo, BrazilNational Institutes of Health: U54 RR19481CAPES: 2284/01-4FAPESP: 2000/03442-4FAPESP: 1999/03688-4Web of Scienc