DNA of Thai Male Thyrotoxic Patients and Family Members

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Investigator: Louis J. Ptacek, MD

Location(s): Thailand

Description

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, except that it is a sporadic condition. The attacks are prevented by treating the underlying hyperthyroidism. Worldwide, TPP is at least 10 times more common than all the familial periodic paralyses together and affects ~10 percent of all thyrotoxic Chinese men. Because of the phenotypic similarity of these conditions, we hypothesized that TPP might also result from mutations in ion channels that were uncovered only with elevated thyroid hormone levels. While sequencing candidate genes, we identified a gene that encodes a novel inwardly rectifying potassium (Kir) channel, Kir2.6. It is highly similar to Kir2.2, expressed in skeletal muscle, and 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 33 percent of the unrelated TPP patients in our collection. Some of these mutations alter a variety of Kir2.6 properties, all of them altering muscle membrane excitability and leading to paralysis.

Louis Ptáček is interested in studies human families with inherited disorders of the nervous system, identifying genes that cause these diseases, and studying both the normal and mutant proteins encoded by some of these genes. Study of these rare, single-gene disorders may yield insights into common and complex diseases. His goal is to understand aspects of normal brain function, including human sleep behavior, and the molecular basis of diseases such as epilepsy and migraine headache. Ultimately, such understanding will lead to better treatments.