Yu‑Long Bao1  · Wei‑Peng Duan1  · Yan Yang1,2 · Zhijie Lin1  · Ying Shen3,4  · Rui Zheng2  · Xin‑Tai Wang1

1 Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China 

2 The Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China 

3 Department of Physiology and Center for Brain Health of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China 

4 Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China

Abstract

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.

Keywords

PKCε; AKT; SHORT syndrome; Cognition; Motor

[SpringerLink]