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Xenopus oocytes used to characterize rare disease caused by potassium channel mutations

Temple-Baraitser Syndrome (TBS) is a rare developmental disorder with only 7 living patients world wide. TBS is characterized by severe mental retardation, facial and limb anomalies, low muscle tone and missing nails on the thumbs and big toes, and most patients also suffer severe epileptic seizures.  Previous studies have shown that TBS patients carry missense mutations within the highly conserved KCNH1 gene. KCNH1 is a voltage-gated potassium channel gene that is predominantly expressed in the central nervous system, so it was a prime candidate for the root cause for epileptic seizures. Drs Cas Simons , Lachlan Rash, and Ryan Taft (Institute for Molecular Bioscience, University of Queensland Australia) and colleagues around the world collaborated to create a genetic profile for six  patients and their parents.

In combination with genomic sequencing of parents and patients, the researchers used the Xenopus oocyte system and in vitro cell lines to investigate how cell function was impacted by KCNH1 mutations. Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function, meaning that the hyperactive potassium channels can result in epilepsy.  Importantly, the study identified some parents of TBS patients carry very low levels of the KCNH1 mutations and these markers can now be used for prenatal genetic screening.

The research findings appeared in a recent issue of Nature Genetics. The study was funded by Australia’s National Health and Medical Research Council, and the Australian Research Council.

Reference:    Simons et al 2015 ‘Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy’ Nature Genetics 47,73–77. doi:10.1038/ng.3153

Click here to view the article at Nature Genetics.

Last Updated: 2015-03-04

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