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

被引:242
作者
Griffith, Elen [1 ]
Walker, Sarah [2 ]
Martin, Carol-Anne [1 ]
Vagnarelli, Paola [3 ]
Stiff, Tom [2 ]
Vernay, Bertrand [1 ]
Al Sanna, Nouriya [4 ]
Saggar, Anand [5 ]
Hamel, Ben [6 ]
Earnshaw, William C. [3 ]
Jeggo, Penny A. [2 ]
Jackson, Andrew P. [1 ]
O'Driscoll, Mark [2 ]
机构
[1] Western Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland
[2] Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England
[3] Univ Edinburgh, Sch Biol Sci, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland
[4] Dhahran Hlth Ctr, Pediat Serv Div, Dhahran, Saudi Arabia
[5] St George Hosp, Sch Med, SW Thames Reg Genet Serv, London SW17 0RE, England
[6] Radboud Univ Nijmegen Med Ctr, Dept Human Genet 417, NL-6525 GA Nijmegen, Netherlands
基金
英国惠康基金; 英国医学研究理事会;
关键词
MICROTUBULE ORGANIZATION; SPINDLE ORGANIZATION; MITOTIC ENTRY; PROTEIN; CENTROSOME; CONTRIBUTES; PATHWAY; MITOSIS; FLORES; PHASE;
D O I
10.1038/ng.2007.80
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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(1,2), is associated with defective ATR-dependent DNA damage signaling(3). Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition(4). 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(5,6). 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 responses(7) or centrosomal function(8,9), may act in common developmental pathways determining human brain and body size.
引用
收藏
页码:232 / 236
页数:5
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