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

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Ryan, Devon P. ^{[1, 2]} ; da Silva, Magnus R. Dias ^[2] ; Soong, Tuck Wah ^{[3, 4]} ; Fontaine, Bertrand ^{[5, 6]} ; Donaldson, Matt R. ^[2] ; Kung, Annie W. C. ^[7] ; Jongjaroenprasert, Wallaya ^[8] ; Liang, Mui Cheng ^[4] ; Khoo, Daphne H. C. ^[9] ; Cheah, Jin Seng ^[10] ; Ho, Su Chin ^[9] ; Bernstein, Harold S. ^[11] ; Maciel, Rui M. B. ^[12] ; Brown, Jr., Robert H. ^[13] ; Ptacek, Louis J. ^{[1, 2, 14]}

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^[1] Univ Calif San Francisco, Grad Program Neurosci, San Francisco, CA 94158 - USA

^[2] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 - USA

^[3] Natl Inst Neurosci, Ion Channel & Transporter Lab, Singapore 308433 - Singapore

^[4] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 308433 - Singapore

^[5] Univ Paris 06, INSERM, UMRS 546, F-75013 Paris - France

^[6] Grp Hosp Pitie Salpetriere, AP HP, Ctr Reference Canalopathies Musculaires, F-75013 Paris - France

^[7] Univ Hong Kong, Queen Mary Hosp, Dept Med, Hong Kong, Hong Kong - Peoples R China

^[8] Mahidol Univ, Ramathibodi Hosp, Dept Med, Bangkok 10400 - Thailand

^[9] Singapore Gen Hosp, Dept Clin Res, Singapore 169608 - Singapore

^[10] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 308433 - Singapore

^[11] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 - USA

^[12] Univ Fed Sao Paulo, Div Endocrinol, Dept Med, BR-04039032 Sao Paulo - Brazil

^[13] Massachusetts Gen Hosp, Charlestown, MA 02129 - USA

^[14] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 - USA

• Tipo de documento: Artigo Científico
• Fonte: Cell; v. 140, n. 1, p. 88-98, JAN 8 2010.
• Citações Web of Science: 130

Resumo

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. (AU)

• Processo FAPESP: 99/03688-4 - Laboratório de sequenciamento no Programa Genoma Humano do Câncer
• Beneficiário: Rui Monteiro de Barros Maciel
• Modalidade de apoio: Auxílio à Pesquisa - Programa GENOMA
• Processo FAPESP: 00/03442-4 - Detecção de mutações no gene do canal de cálcio (CACNl 1A3) em pacientes com paralisia periódica hipocalêmica tirotóxica
• Beneficiário: Magnus Régios Dias da Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado