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Disruption of Mouse Cenpj, a Regulator of Centriole Biogenesis, Phenocopies Seckel Syndrome

McIntyre, R E and Ismail, O and Carragher, D M and Sanchez-Andrade, G and Del Castillo Velasco Herrera, M and Edwards, A and Ramirez-Solis, R and Gallagher, R P and Logan, D and Arends, M and Tsang, S and Mahajan, V and Scudamore, C L and White, J and Adams, D J (2012) Disruption of Mouse Cenpj, a Regulator of Centriole Biogenesis, Phenocopies Seckel Syndrome. PLoS Genetics, 8 (11). e1003022.

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Abstract

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.

Item Type: Article
RVC Publication Type: Research (full) paper
WoS ID: 000311891600013
DOI: https://doi.org/10.1371/journal.pgen.1003022
Departments: Pathobiology and Population Sciences
Depositing User: RVC Auto-import
Date Deposited: 12 Nov 2014 16:13
Last Modified: 30 Nov 2018 12:12
URI: http://researchonline.rvc.ac.uk/id/eprint/6401