Kctd7 deficiency induces myoclonic seizures associated with Purkinje cell death and microvascular defects

Abstract

Mutations in the potassium channel tetramerization domain-containing 7 (KCTD7) gene are associated with a severe neurodegenerative phenotype characterized by childhood onset of progressive and intractable myoclonic seizures accompanied by developmental regression. Kctd7 (EPM3) is a member of a large family of progressive myoclonic epilepsy (EPM) syndromes displaying a broad spectrum of clinical severity. Animal models of Kctd7-related disease are lacking, and little is known regarding how Kctd7 protein defects lead to epilepsy and cognitive dysfunction. We characterized brain Kctd7 expression patterns during development and show it is selectively enriched in specific regions as the brain matures. We further demonstrate that Kctd7-deficient mice develop seizures and locomotor defects with features similar to those observed in human KCTD7-associated disease. We also show that Kctd7 is required for Purkinje cell survival in the cerebellum and that selective degeneration of these neurons is accompanied by defects in cerebellar brain microvascular organization and patterning. Together, these results define a new model for Kctd7- associated epilepsy and identify Kctd7 as a modulator of neuron survival and excitability linked to microvascular alterations in vulnerable regions.