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

Authors: Griffith, E  Walker, S  Martin, CA  Vagnarelli, P  Stiff, T  Vernay, B  Al Sanna, N  Saggar, A  Hamel, B  Earnshaw, WC  Jeggo, PA  Jackson, AP  O'Driscoll, M 
Citation: Griffith E, etal., Nat Genet. 2008 Feb;40(2):232-6. Epub 2007 Dec 23.
Pubmed: (View Article at PubMed) PMID:18157127
DOI: Full-text: DOI:10.1038/ng.2007.80

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.


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CRRD Object Information
CRRD ID: 11537403
Created: 2016-10-04
Species: All species
Last Modified: 2016-10-04
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.