Hussain et al. (2012) reported 2 sibs, born of consanguineous Pakistani parents, with primary microcephaly apparent at birth. Each had a sloping forehead, retrognathia, severe cognitive deficits, and unintelligible speech at age 5 years. One died at age ... Hussain et al. (2012) reported 2 sibs, born of consanguineous Pakistani parents, with primary microcephaly apparent at birth. Each had a sloping forehead, retrognathia, severe cognitive deficits, and unintelligible speech at age 5 years. One died at age 11 years. The head circumferences ranged between -12 and -14.5 SD. No other abnormalities were noted.
In 2 sibs, born of consanguineous Pakistani parents, with autosomal recessive primary microcephaly-8, Hussain et al. (2012) identified a homozygous truncating mutation in the CEP135 gene (611423.0001). The mutation was identified by genomewide linkage analysis followed by candidate ... In 2 sibs, born of consanguineous Pakistani parents, with autosomal recessive primary microcephaly-8, Hussain et al. (2012) identified a homozygous truncating mutation in the CEP135 gene (611423.0001). The mutation was identified by genomewide linkage analysis followed by candidate gene sequencing, and was not found in 384 Pakistani controls. Whole-exome sequencing of 1 of the patients did not identify other potentially pathogenic mutations that could be responsible for the disorder. The parents were healthy with normal head circumference; the father carried the mutation in heterozygous state. Cultured patient fibroblasts showed poor growth and had increased numbers of fragmented centrosomes per cell compared to controls. The microtubule network was frequently disorganized (55% of the cells) and showed cell shape changes as well as misshapen and fragmented nuclei. Approximately 22% of mutant patient fibroblasts were without centrosomes, which was never observed in control cells. In vitro functional expression studies of the mutant protein in COS-7 cells caused abnormal disorganized microtubule networks, and the mutant protein did not localize to the centrosome. The findings indicated that CEP135 is an essential component of the centrosome.