Griffith, E., Walker, S., Martin, C.A., Vagnarelli, P., Stiff, T., Vernay, B., Al Sanna, N., Saggar, A., Hamel, B., Earnshaw, W.C., Jeggo, P.A., Jackson, A.P. and O'Driscoll, M. (2008) Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nature Genetics, 40 (2). pp. 232-236. ISSN 1061-4036
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Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size, is associated with defective ATR-dependent DNA damage signaling. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition. We now report that mutations in the gene encoding pericentrin (PCNT)--resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins--also cause Seckel syndrome. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function may act in common developmental pathways determining human brain and body size.
|Keywords:||Amino Acid Sequence Antigens/chemistry/*genetics/physiology Base Sequence Case-Control Studies Cell Cycle Proteins/genetics Cell Line Chromosomes, Human, Pair 22 Codon Codon, Nonsense Consanguinity *DNA Damage Exons Frameshift Mutation Genes, Recessive Genome, Human Homozygote Humans Linkage (Genetics) Lod Score Lymphocytes/metabolism Microcephaly/*genetics Models, Biological Molecular Sequence Data Molecular Weight Mutagenesis, Insertional *Mutation Oligonucleotide Array Sequence Analysis Physical Chromosome Mapping Polymorphism, Single Nucleotide Protein Isoforms/chemistry/genetics Protein Structure, Tertiary Protein-Serine-Threonine Kinases/genetics RNA Interference RNA, Small Interfering/metabolism Sequence Analysis, DNA Signal Transduction/*genetics/physiology|
|Depositing User:||Gee Wheatley|
|Date Deposited:||17 Jul 2008|
|Last Modified:||07 Mar 2017 02:01|
|Google Scholar:||87 Citations|