CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate

Abstract

CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2- and Casp-specific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that CUX2 and CASP variants contribute to the TLE pathology through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus.

Integrative single-cell characterization of hypothalamus sex-differential and obesity-associated genes and regulatory elements

“…We also found enrichment for the forkhead box P1 (FOXP1) motif and the NeuroD family of basic helix-loop-helix 1 (NEUROD1) motif, both known to regulate glutamatergic neurogenesis 75,76 ( Fig.3a ). In addition, we found the TFBS for cutlike homeobox 1 (CUX1), which controls neuronal proliferation, dendrite branching and synapse formation to be enriched in GABAergic neurons 77 ( Fig.3a ). Dopamine neurons showed enrichment for FOXA1/FOXA2 motifs, known to be associated with dopamine biosynthesis 78 .…”

“…3a). In addition, we found the TFBS for cutlike homeobox 1 (CUX1), which controls neuronal proliferation, dendrite branching and synapse formation to be enriched in GABAergic neurons 77 (Fig. 3a).…”

Machine Learning Analysis of Alzheimer’s Disease Single-Cell RNA-Sequencing Data across Cortex and Hippocampus Regions

“…Cut-like homeobox 2 (Cux2) is a transcription factor that plays a role in dendrite and spine development, as well as synapse formation in projection neurons located in the upper neocortical layers of mice. When CUX2 is deficient, it leads to increased facilitation of excitatory synaptic transmission onto the hippocampus and heightened susceptibility to seizures induced by kainite [40]. Evidence of early-determined Cux2-positive neuronal precursors has been observed in the subventricular zone (SVZ) and intermediate zone (IZ), as well as in upper-layer neurons.…”

CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

“…A recurrent de novo missense variant within the first CUT repeat of CUX2 causes CUX2 -related epileptic encephalopathy [ 32 ]. Recent reports found other CUX2 missense variants as genetic contributors to kainic acid-induced epilepsy [ 33 ]. Although the number of individuals with missense variants is very low, it is striking that all of them had seizures (Table 1 ).…”