Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome.
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...
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2012
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oai:doaj.org-article:59c11391f61449a4aa008d3e380c5a642021-11-18T06:20:33ZDisruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome.1553-73901553-740410.1371/journal.pgen.1003022https://doaj.org/article/59c11391f61449a4aa008d3e380c5a642012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23166506/pdf/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Disruption 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 (Cenpj(tm/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 Cenpj(tm/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, Cenpj(tm/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.Rebecca E McIntyrePavithra Lakshminarasimhan ChavaliOzama IsmailDamian M CarragherGabriela Sanchez-AndradeJosep V FormentBeiyuan FuMartin Del Castillo Velasco-HerreraAndrew EdwardsLouise van der WeydenFengtang YangSanger Mouse Genetics ProjectRamiro Ramirez-SolisJeanne EstabelFerdia A GallagherDarren W LoganMark J ArendsStephen H TsangVinit B MahajanCheryl L ScudamoreJacqueline K WhiteStephen P JacksonFanni GergelyDavid J AdamsPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 8, Iss 11, p e1003022 (2012) |
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Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 Rebecca E McIntyre Pavithra Lakshminarasimhan Chavali Ozama Ismail Damian M Carragher Gabriela Sanchez-Andrade Josep V Forment Beiyuan Fu Martin Del Castillo Velasco-Herrera Andrew Edwards Louise van der Weyden Fengtang Yang Sanger Mouse Genetics Project Ramiro Ramirez-Solis Jeanne Estabel Ferdia A Gallagher Darren W Logan Mark J Arends Stephen H Tsang Vinit B Mahajan Cheryl L Scudamore Jacqueline K White Stephen P Jackson Fanni Gergely David J Adams Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome. |
| description |
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 (Cenpj(tm/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 Cenpj(tm/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, Cenpj(tm/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. |
| format |
article |
| author |
Rebecca E McIntyre Pavithra Lakshminarasimhan Chavali Ozama Ismail Damian M Carragher Gabriela Sanchez-Andrade Josep V Forment Beiyuan Fu Martin Del Castillo Velasco-Herrera Andrew Edwards Louise van der Weyden Fengtang Yang Sanger Mouse Genetics Project Ramiro Ramirez-Solis Jeanne Estabel Ferdia A Gallagher Darren W Logan Mark J Arends Stephen H Tsang Vinit B Mahajan Cheryl L Scudamore Jacqueline K White Stephen P Jackson Fanni Gergely David J Adams |
| author_facet |
Rebecca E McIntyre Pavithra Lakshminarasimhan Chavali Ozama Ismail Damian M Carragher Gabriela Sanchez-Andrade Josep V Forment Beiyuan Fu Martin Del Castillo Velasco-Herrera Andrew Edwards Louise van der Weyden Fengtang Yang Sanger Mouse Genetics Project Ramiro Ramirez-Solis Jeanne Estabel Ferdia A Gallagher Darren W Logan Mark J Arends Stephen H Tsang Vinit B Mahajan Cheryl L Scudamore Jacqueline K White Stephen P Jackson Fanni Gergely David J Adams |
| author_sort |
Rebecca E McIntyre |
| title |
Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome. |
| title_short |
Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome. |
| title_full |
Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome. |
| title_fullStr |
Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome. |
| title_full_unstemmed |
Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome. |
| title_sort |
disruption of mouse cenpj, a regulator of centriole biogenesis, phenocopies seckel syndrome. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/59c11391f61449a4aa008d3e380c5a64 |
| work_keys_str_mv |
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