Open AccessAn epilepsy-associated K V 1.2 charge-transfer-center mutation impairs K V 1.2 and K V 1.4 trafficking
Author(s) -
Michelle Nilsson,
Sivert Lindström,
Maki Kaneko,
Kaiqian Wang,
Teresa Mínguez-Viñas,
Marina Angelini,
Federica Steccanella,
Deborah Holder,
Michela Ottolia,
Riccardo Olcese,
Antonios Pantazis
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2113675119
Subject(s) - mutation , mutant , potassium channel , gene , protein subunit , biology , genetics , microbiology and biotechnology , biophysics
Significance A child with epilepsy has a previously unreported, heterozygous mutation inKCNA2 , the gene encoding KV 1.2 proteins. Four KV 1.2 assemble into a potassium-selective channel, a protein complex at the neuronal cell surface regulating electrical signaling. KV 1.2 subunits assemble with other KV 1-family members to form heterotetrameric channels, contributing to neuronal potassium-channel diversity. The most striking consequence of this mutation is preventing KV 1.2-subunit trafficking, i.e., their ability to reach the cell surface. Moreover, the mutation is dominant negative, as mutant subunits can assemble with wild-type KV 1.2 and KV 1.4, trapping them into nontrafficking heterotetramers and decreasing their functional expression. Thus, KV 1-family genes’ ability to form heterotetrameric channels is a double-edged sword, rendering KV 1-family members vulnerable to dominant-negative mutations in a single member gene.