COL4A2 is the encoding gene of the α2 chains of type IV collagen, and
missense mutations of COL4A2 is correlated with multiple diseases.
However, the association of COL4A2 mutations with epilepsy remains
elusive. Here, we aimed to explore the function of COL4A2 mutations in
the development of epilepsy. We performed a full spectrum of
family-enhanced whole-exome sequencing on a family lineage and examined
the genetic change on COL4A2 gene. The kainic acid (KA)-induced in vivo
model and lipopolysaccharide (LPS)-induced in vitro model were
established. The production and secretion of inflammation cytokines were
measured by qPCR, western blotting, and ELISA assay. Neuron damages and
astrocyte activation were checked by Nissle and GFAP immunofluorescence
staining. One heterozygous variant was detected in the COL4A2 gene:
c.1148C>T(p.Pro383Leu). COL4A2 mutation significant induced
the exacerbation of seizures and impaired the learning and memory
phenotype of the KA rats. COL4A2 mutation promoted the hippocampal
astrocyte activation, enhanced hippocampal neuronal injury in the rats.
The levels of iNOS, COX-2, IL-1β, IL-6, and TNF-α elevated in KA-treated
rats and LPS-treated astrocytes were further induced by COL4A2 mutation.
Mechanically, COL4A2 mutation stimulated JAK/STAT signaling. JAK2 and
STAT3 phosphorylation was promoted by COL4A2 mutation and JAK/STAT
signaling inhibitor WP1066 could blocked the effect in primary
astrocytes and CTX-TNA cells. These data indicated that a new identified
COL4A2 mutation contributed to astrocyte activation by activating
JAK/STAT signaling in epilepsy. Our findings provided a novel mechanism
and treatment target of COL4A2 related epilepsy.