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

Publisher Website
Google Scholar
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 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.