Extracellular Kir2.1^C122Y Mutant Upsets Kir2.1-PIP₂ Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome.

ABSTRACT:

Background

Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K⁺ channel Kir2.1. The extracellular Cys (cysteine)₁₂₂-to-Cys₁₅₄ disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys₁₂₂-to-Cys₁₅₄ disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state.

Methods

We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we genera

SUBMITTER: Cruz FM 

PROVIDER: S-EPMC11009053 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature