Awad et al. (2013) reported a 12-year-old girl and her 6-year old brother, born of related Saudi parents, with primary microcephaly (-5.8 and -4.3 SD, respectively) and low-normal cognitive function. Brain MRI was normal except for small brain ... Awad et al. (2013) reported a 12-year-old girl and her 6-year old brother, born of related Saudi parents, with primary microcephaly (-5.8 and -4.3 SD, respectively) and low-normal cognitive function. Brain MRI was normal except for small brain size. The sister and brother also had short stature (-3.6 SD and -2.3 SD, respectively).
In 2 sibs with MCPH11, Awad et al. (2013) identified a homozygous mutation in the PHC1 gene (L992F; 602978.0001). The mutation, which was found by homozygosity mapping combined with exome sequencing, segregated with the disorder and was not ... In 2 sibs with MCPH11, Awad et al. (2013) identified a homozygous mutation in the PHC1 gene (L992F; 602978.0001). The mutation, which was found by homozygosity mapping combined with exome sequencing, segregated with the disorder and was not found in the dbSNP, Exome Variant Server, or 1000 Genomes database or in 199 Saudi exomes or 554 Saudi control individuals. Patient cells showed normal amounts of mutant PHC1 mRNA, but a significant reduction (about 72%) in mutant protein levels, which was shown to result from proteosome-mediated degradation. Patient cells showed increased expression of geminin (GMNN; 602842) and decreased interaction between PHC1 and ubiquitinated H2A (613499) compared to control cells. These changes were replicated by siRNA against PHC1. Patient cells also showed an increase in DNA damage and defective DNA repair in response to irradiation, as well as abnormal cell cycle activity consistent with reduced proliferative activity, compared to controls. These defects were associated with abnormalities in chromatin regulation, and could be rescued in patient cells by overexpression of wildtype PHC1. Gene microarray analysis of patient cells showed dysregulation of a large number of genes involved in cell cycle regulation. The findings highlighted a role for chromatin remodeling in the pathogenesis of primary microcephaly.