title: Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome.
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 (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.
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: McIntyre
authors.forename: Pavithra
authors.initials: P
authors.lastname: Lakshminarasimhan Chavali
authors.forename: Ozama
authors.initials: O
authors.lastname: Ismail
authors.forename: Damian M
authors.initials: DM
authors.lastname: Carragher
authors.forename: Gabriela
authors.initials: G
authors.lastname: Sanchez-Andrade
authors.forename: Josep V
authors.initials: JV
authors.lastname: Forment
authors.forename: Beiyuan
authors.initials: B
authors.lastname: Fu
authors.forename: Martin
authors.initials: M
authors.lastname: Del Castillo Velasco-Herrera
authors.forename: Andrew
authors.initials: A
authors.lastname: Edwards
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weyden
authors.forename: Fengtang
authors.initials: F
authors.lastname: Yang
authors.forename: Ramiro
authors.initials: R
authors.lastname: Ramirez-Solis
authors.forename: Jeanne
authors.initials: J
authors.lastname: Estabel
authors.forename: Ferdia A
authors.initials: FA
authors.lastname: Gallagher
authors.forename: Darren W
authors.initials: DW
authors.lastname: Logan
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Tsang
authors.forename: Vinit B
authors.initials: VB
authors.lastname: Mahajan
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Scudamore
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: White
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
authors.forename: Fanni
authors.initials: F
authors.lastname: Gergely
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
mesh_terms: D000818:Animals; D017209:Apoptosis; D002502:Centrioles / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004392:Dwarfism / Q000235:genetics / Q000503:physiopathology; D047108:Embryonic Development / Q000235:genetics*; D019066:Facies; D042822:Genomic Instability; D051379:Mice; D008822:Mice, Transgenic; D008831:Microcephaly / Q000235:genetics / Q000503:physiopathology; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008938:Mitosis / Q000235:genetics; D009154:Mutation; D015398:Signal Transduction / Q000235:genetics; D008941:Spindle Apparatus / Q000235:genetics
chemical_list: C580968:Cenpj protein, mouse; D008869:Microtubule-Associated Proteins