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


Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size1,2, is associated with defective ATR-dependent DNA damage signaling3. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition4. 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 syndrome5,6. 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 responses7 or centrosomal function8,9 may act in common developmental pathways determining human brain and body size.

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Figure 1: Schematic of the Sckl4 critical region and the PCNT gene depicting location of identified mutations.
Figure 2: Pericentrin localization and function is disrupted in PCNT-Seckel cell lines.
Figure 3: PCNT is required for ATR-dependent DNA damage signaling.
Figure 4: Model of pericentrin's role in ATR-dependent G2-M checkpoint arrest.

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We thank the families and their clinicians for their participation in this study; C. Hayward for contributing control samples; S. McKay and the MRC HGU core sequencing service for advice and technical support; C. Nicol for help with figure preparation; X. Fant, V. Van Heyningen and N. Hastie for discussions and comments; W. Fergusson (St. Mary's Hospital, Manchester) for LCL transformation; and A. Merdes and J. Salisbury for kindly sharing antibody reagents. A.P.J.'s laboratory is funded by the MRC, M.O'D.'s laboratory is funded by CRUK and the MRC, and P.A.J.'s laboratory is funded by the MRC, UK LRF, IACR and EU grants (FIGH-CT-200200207) (DNA repair) and FI6R-CT-2003-508842 (RiscRad). P.V. and W.C.E. are funded by the Wellcome Trust, of which W.C.E. is a Principal Research Fellow. A.P.J. is an MRC Senior Clinical Fellow and M.O'D. is a CRUK Senior Cancer Research Fellow.

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E.G., C.-A.M. and A.P.J. performed the mutation screening and sequencing of controls; A.P.J., linkage analysis; P.V., immunostaining analysis of LCLs and C.-A.M., immunoblotting. S.W., T.S., M.O'D. and P.A.J. designed and performed the DNA damage response assays and RNAi experiments. N.A.S., A.S. and B.H. provided clinical samples and data. E.G. and A.P.J. wrote the paper with M.O'D., P.A.J., B.V. and W.C.E.

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Correspondence to Andrew P Jackson.

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Griffith, E., Walker, S., Martin, CA. et al. Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat Genet 40, 232–236 (2008).

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