Key result
Expression of the Kv7.2-M547V variant in mice induced early mortality, spontaneous seizures, memory impairment, and widespread neurodegeneration.
Why the study?
Multiple epileptic encephalopathy mutations in the intracellular calmodulin-binding domain of Kv7.2 decrease surface expression of axonal Kv7 channels, but their in vivo effects remained to be investigated.
Abnormal Kv7 surface expression due to the M547V mutation is implicated as a key etiology of KCNQ2-associated epileptic encephalopathy.
M547V knockin mice exhibit KCNQ2 encephalopathy features; hypothesis-generating for Kv7 trafficking defects as therapeutic targets.
Significance Epileptic encephalopathy (EE) is a devastating neurologic disorder characterized by early-onset seizures with severe cognitive and psychomotor impairments. EE is associated with dominant mutations in the KCNQ2 gene which encodes the K v 7.2 subunit of K v 7 potassium channels. Previously, we reported that multiple EE mutations in the intracellular calmodulin-binding domain of K v 7.2 decreased surface expression of axonal K v 7 channels critical for suppressing neuronal excitability. Here, we generated conditional knockin mice carrying one of these mutations, M547V. These mice displayed spontaneous seizures, cognitive impairment, neurodegeneration, and reactive astrogliosis, implicating abnormal K v 7 surface expression as a key etiology of KCNQ2 -associated EE.
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Kim et al. (2021) studied Epileptic encephalopathy (n=1,098). Kv7.2-M547V variant expression vs. Wild-type / control mice was evaluated on Spontaneous seizures, mortality, and cognitive/behavioral impairments. Expression of the Kv7.2-M547V variant in mice induced early mortality, spontaneous seizures, memory impairment, and widespread neurodegeneration.
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