Abstract
Primary microcephaly (PM) is a developmental disorder of early neuroprogenitors that results in reduction of the brain mass, particularly the cortex. To gain fresh insight into the pathogenesis of PM, we describe a consanguineous family with a novel genetic variant responsible for the disease. We performed autozygosity mapping followed by exome sequencing to detect the causal genetic variant. Several functional assays in cells expressing the wild-type or mutant gene were performed to understand the pathogenesis of the identified mutation. We identify a novel mutation in PHC1, a human orthologue of the Drosophila polyhomeotic member of polycomb group (PcG), which significantly decreases PHC1 protein expression, increases Geminin protein level and markedly abolishes the capacity to ubiquitinate histone H2A in patient cells. PHC1 depletion in control cells similarly enhances Geminin expression and decreases histone H2A ubiquitination. The ubiquitination defect and accumulation of Geminin with consequent defect in cell cycle are rescued by over-expression of PHC1 in patient cells. Although patients with the PHC1 mutation exhibit PM with no overt progression of the disease, patient cells also show aberrant DNA damage repair, which is rescued by PHC1 overexpression. These findings reveal several cellular defects in cells carrying the PHC1 mutation and highlight the role of chromatin remodeling in the pathogenesis of PM.