PCNT_Seckel_Nat_Genet_2008.pdf (116.26 kB)
Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling
journal contribution
posted on 2023-06-07, 14:44 authored by Elen Griffith, Sarah Walker, Carol-Anne Martin, Paola Vagnarelli, Thomas StiffThomas Stiff, Bertrand Vernay, Nouriya Al Sanna, Anand Saggar, Ben Hamel, William C Earnshaw, Penny Jeggo, Andrew P Jackson, Mark O'DriscollMark O'DriscollLarge 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.
History
Publication status
- Published
File Version
- Accepted version
Journal
Nature GeneticsISSN
1061-4036Publisher
Nature Publishing GroupExternal DOI
Issue
2Volume
40Page range
232-236Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2008-07-30First Open Access (FOA) Date
2018-05-08First Compliant Deposit (FCD) Date
2018-05-08Usage metrics
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No categories selectedKeywords
Amino Acid Sequence Antigens/chemistry/*genetics/physiology Base Sequence Case-Control Studies Cell Cycle Proteins/genetics Cell Line ChromosomesHumanPair 22 Codon CodonNonsense Consanguinity *DNA Damage Exons Frameshift Mutation GenesRecessive GenomeHuman Homozygote Humans Linkage (Genetics) Lod Score Lymphocytes/metabolism Microcephaly/*genetics ModelsBiological Molecular Sequence Data Molecular Weight MutagenesisInsertional *Mutation Oligonucleotide Array Sequence Analysis Physical Chromosome Mapping PolymorphismSingle Nucleotide Protein Isoforms/chemistry/genetics Protein StructureTertiary Protein-Serine-Threonine Kinases/genetics RNA Interference RNASmall Interfering/metabolism Sequence AnalysisDNA Signal Transduction/*genetics/physiology
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