Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis
Salma Awad1, Mohammed S Al-Dosari, Nadya Al-Yacoub
1Department of Genetics, Developmental Genetics Unit.
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.
Insights
A novel mutation in PHC1 causes primary microcephaly (PM), a brain development disorder. This genetic variant disrupts histone ubiquitination and cell cycle regulation, impacting neuroprogenitor cells.
Area of Science:
- Genetics
- Developmental Biology
- Neuroscience
Background:
- Primary microcephaly (PM) is a severe neurodevelopmental disorder characterized by reduced brain size, particularly the cerebral cortex.
- The underlying genetic causes of PM are diverse, highlighting the complexity of early brain development.
Purpose of the Study:
- To investigate the genetic basis and cellular mechanisms of a novel form of primary microcephaly.
- To identify the specific gene and mutation responsible for PM in a consanguineous family.
Main Methods:
- Autozygosity mapping and exome sequencing were employed to identify the causative genetic variant.
- Functional assays were conducted on patient-derived cells expressing wild-type and mutant PHC1.
- Cellular processes including protein expression, histone modification, cell cycle progression, and DNA damage repair were analyzed.
Main Results:
- A novel mutation in PHC1, a polycomb group gene, was identified as the cause of PM.
- The mutation leads to decreased PHC1 protein, increased Geminin levels, and impaired histone H2A ubiquitination in patient cells.
- Patient cells exhibit cell cycle defects and aberrant DNA damage repair, which are rescued by PHC1 re-expression.
Conclusions:
- The findings reveal that mutations in PHC1 disrupt chromatin remodeling, leading to cellular defects underlying primary microcephaly.
- This study underscores the critical role of PHC1 and histone ubiquitination in neurodevelopment and cell cycle regulation.
- Aberrant DNA damage repair is a newly identified cellular consequence of PHC1 mutations in PM.
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