Kctd7 Deficiency Induces Myoclonic Seizures Associated With Purkinje Cell Death and Microvascular Defects

Authors

Justine H Liang
Jonathan Alevy
Viktor Akhanov
Ryan Seo
Cory A Massey
Danye Jiang
Joy Zhou
Roy V Sillitoe
Jeffrey L Noebels
Melanie A Samuel

Publication Date

9-1-2022

Journal

Disease Models & Mechanisms

PMID

35972048

PMCID

PMC9509889

PubMedCentral® Posted Date

9-13-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Child, Humans, Mice, Myoclonic Epilepsies, Progressive, Phenotype, Potassium Channels, Purkinje Cells, Seizures, Kctd7, Epilepsy, Seizure, Motor defects, Cerebellum, Vasculature

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-driven disease is part of a large family of progressive myoclonic epilepsy 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 Kctd7 expression patterns in the mouse brain during development and show that 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 diseases. 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 microvascular organization and patterning. Taken 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.