title: Cellular and clinical impact of haploinsufficiency for genes involved in ATR signaling.
abstract: Ataxia telangiectasia and Rad3-related (ATR) protein, a kinase that regulates a DNA damage-response pathway, is mutated in ATR-Seckel syndrome (ATR-SS), a disorder characterized by severe microcephaly and growth delay. Impaired ATR signaling is also observed in cell lines from additional disorders characterized by microcephaly and growth delay, including non-ATR-SS, Nijmegen breakage syndrome, and MCPH1 (microcephaly, primary autosomal recessive, 1)-dependent primary microcephaly. Here, we examined ATR-pathway function in cell lines from three haploinsufficient contiguous gene-deletion disorders--a subset of blepharophimosis-ptosis-epicanthus inversus syndrome, Miller-Dieker lissencephaly syndrome, and Williams-Beuren syndrome--in which the deleted region encompasses ATR, RPA1, and RFC2, respectively. These three genes function in ATR signaling. Cell lines from these disorders displayed an impaired ATR-dependent DNA damage response. Thus, we describe ATR signaling as a pathway unusually sensitive to haploinsufficiency and identify three further human disorders displaying a defective ATR-dependent DNA damage response. The striking correlation of ATR-pathway dysfunction with the presence of microcephaly and growth delay strongly suggests a causal relationship.
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton, UK. m.o-driscoll@sussex.ac.uk
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Johanna M
authors.initials: JM
authors.lastname: van Hagen
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D016569:Blepharophimosis / Q000235:genetics; D001763:Blepharoptosis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D002460:Cell Line; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D004392:Dwarfism / Q000235:genetics*; D017353:Gene Deletion; D006238:Haploidy; D006801:Humans; D008831:Microcephaly / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051716:Replication Protein A / Q000235:genetics; D051818:Replication Protein C / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013577:Syndrome; D018980:Williams Syndrome / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C497561:RFC2 protein, human; D034741:RNA, Small Interfering; C497167:RPA1 protein, human; D051716:Replication Protein A; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D051818:Replication Protein C