Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling

Elen Griffith, Sarah Walker, Carol-Anne Martin, Paola Vagnarelli, Tom Stiff, Bertrand Vernay, Nouriya Al Sanna, Anand Saggar, Ben Hamel, William C Earnshaw, Penny A Jeggo, Andrew P Jackson, Mark O'Driscoll

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)232-236
Number of pages5
JournalNature Genetics
Volume40
Issue number2
Early online date23 Dec 2007
DOIs
Publication statusPublished - Feb 2008

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