Primary microcephaly (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a markedly reduced head circumference, simplified brain gyri, and varying degrees of intellectual disability. To date, more than 20 genes have been implicated in MCPH. Among these, CEP135(Centrosomal Protein 135 kDa), located on chromosome 4q12, represents one of the key genes associated with autosomal recessive primary microcephaly (MCPH8). The CEP135 protein is a core structural component of the centrosome that plays a crucial role in centriole biogenesis, spindle formation, and maintenance of centrosome integrity during neurogenesis.
In this study, 33 Pakistani families with clinically diagnosed primary microcephaly were evaluated for linkage to known MCPH loci using microsatellite markers. Several families demonstrated linkage to the MCPH8 locus, indicating a likely involvement of CEP135variants in this cohort. Subsequent direct sequencing of the CEP135gene revealed both previously known and novel pathogenic mutations. These included missense, nonsense, and frameshift variants, many of which co-segregated with the disease phenotype but were absent in 200 ethnically matched control chromosomes.
Clinically, affected individuals with CEP135-related microcephaly typically present with severe congenital microcephaly, global developmental delay, and intellectual disability. Neuroimaging findings often show reduced cerebral volume, simplified gyral patterns, and variable cortical malformations, including hypoplasia of the corpus callosum or cerebellum. Functional studies indicate that loss-of-function mutations in CEP135lead to defective centriole duplication and abnormal spindle assembly, resulting in impaired neural progenitor proliferation and premature neuronal depletion.
These findings underscore the essential role of CEP135 in centrosome organization and cortical development, further highlighting the genetic heterogeneity and molecular complexity of primary microcephaly across diverse populations.
CEP135