Deletion of the SHORT Syndrome Gene Prkce Results in Brain Atrophy and Cognitive and Motor Behavior Deficits in Mice.

The neurological manifestations of SHORT syndrome include intrauterine growth restriction, microcephaly, intellectual disability, hearing loss, and speech delay. SHORT syndrome is generally believed to be caused by PIK3R1 gene mutations and impaired PI3K-AKT activation. Recently, a clinical case report described a SHORT syndrome with a novel mutant in PRKCE gene encoding protein kinase Cε (PKCε). However, it remains unclear whether the down-regulation of PKCε gives rise to the symptoms of SHORT syndrome. In this study, we show that a deficiency of PKCε in the central nervous system leads to cerebral and cerebellar atrophy, as well as motor and social deficits. Mechanistically, the deletion of PKCε results in the down-regulation of VEGF/PI3K-induced AKT activation, thereby causing abnormal brain development and dysfunctions. These findings emphasize the roles of PKCε in the development and function of the brain, and offer new perspectives for understanding the neurological manifestations of SHORT syndrome.