Disruption of the centromere protein J gene, CENPJ (CPAP, MCPH6, SCKL4), which is a highly conserved and ubiquitiously expressed centrosomal protein, has been associated with primary microcephaly and the microcephalic primordial dwarfism disorder Seckel syndrome. The mechanism by which disruption of CENPJ causes the proportionate, primordial growth failure that is characteristic of Seckel syndrome is unknown. By generating a hypomorphic allele of Cenpj, we have developed a mouse (Cenpjtm/tm) that recapitulates many of the clinical features of Seckel syndrome, including intrauterine dwarfism, microcephaly with memory impairment, ossification defects, and ocular and skeletal abnormalities, thus providing clear confirmation that specific mutations of CENPJ can cause Seckel syndrome. Immunohistochemistry revealed increased levels of DNA damage and apoptosis throughout Cenpjtm/tm embryos and adult mice showed an elevated frequency of micronucleus induction, suggesting that Cenpj-deficiency results in genomic instability. Notably, however, genomic instability was not the result of defective ATR-dependent DNA damage signaling, as is the case for the majority of genes associated with Seckel syndrome. Instead, Cenpjtm/tm embryonic fibroblasts exhibited irregular centriole and centrosome numbers and mono- and multipolar spindles, and many were near-tetraploid with numerical and structural chromosomal abnormalities when compared to passage-matched wild-type cells. Increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism that is associated with CENPJ-Seckel syndrome.
Mutation of the gene CENPJ has been found to cause primary microcephaly, an inherited disorder that is characterised by severely reduced brain size. More recently, mutation of CENPJ has been associated with Seckel syndrome, a disorder that is characterised by a severe reduction in both brain and body size that is apparent at birth, mental retardation, and skeletal abnormalities, in addition to a number of other clinical manifestations. Here, we have generated a mouse that expresses only low levels of mouse Cenpj protein and find that it recapitulates many of the key features of Seckel syndrome. Moreover, we find that errors during the proliferation of Cenpjtm/tm cells frequently lead to abnormal numbers of chromosomes or damaged chromosomes, which is likely to be the cause of increased cell death during embryonic development and to contribute to the proportionate dwarfism that is characteristic of Seckel syndrome.