Thyrotoxic Periodic Paralysis, Susceptibility To, 2

A number sign (#) is used with this entry of evidence that susceptibility to thyrotoxic periodic paralysis-2 (TTPP2) is conferred by variation in the KCNJ18 gene (613236) on chromosome 17p11.

For a general phenotypic description and a discussion of genetic heterogeneity of susceptibility to thyrotoxic periodic paralysis, see 188580.

Clinical Features

Ryan et al. (2010) evaluated patients with TTPP, as characterized by episodic flaccid paralysis, hypokalemia during the attacks, and laboratory evidence of thyrotoxicosis.

Molecular Genetics

Ryan et al. (2010) identified 6 different mutations in the KCNJ18 gene in patients with thyrotoxic periodic paralysis. Four of the mutations (613236.0001-613236.0004) were found to confer susceptibility to the disorder. Although the 2 other mutations were identified in multiple patients, R399X in 7 (26%) of 27 patients from Singapore and Q407X in 5 patients, functional expression studies showed that both of these mutant channels were functional in 293T cells and localized correctly to the membrane. The putative disease-causing effects of these mutants were not clear. None of the 6 mutations identified altered the channel's inward rectifying activity, but in vitro studies indicated that the point mutations resulted in altered channel dynamics under thyrotoxic conditions. The findings suggested that variations in the KCNJ18 gene may cause predisposition to episodic weakness seen only during thyrotoxicosis.