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PCNT_Seckel_Nat_Genet_2008.pdf (116.26 kB)

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

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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'Driscoll
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.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Nature Genetics

ISSN

1061-4036

Publisher

Nature Publishing Group

Issue

2

Volume

40

Page range

232-236

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2008-07-30

First Open Access (FOA) Date

2018-05-08

First Compliant Deposit (FCD) Date

2018-05-08