Cellular and clinical impact of haploinsufficiency for genes involved in ATR-signalling

Ataxia telangiectasia and Rad3-related (ATR), a kinase that regulates a DNA damage response pathway, is mutated in ATR-Seckel Syndrome (ATR-SS), a disorder characterised by severe microcephaly and growth delay. Impaired ATR-signalling is also observed in cell lines from additional disorders characterised by microcephaly and growth delay, including non-ATR SS, Nijmegen Breakage Syndrome and MCPH1-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 or RFC2 respectively. These three genes function in ATR-signalling. Cell lines from these disorders displayed an impaired ATRdependent DNA damage response. Thus, we describe ATR-signalling 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.