Cellular and clinical impact of Haploinsufficiency for genes involved in ATR signaling

O'Driscoll, Mark, Dobyns, William B, van Hagen, Johanna M and Jeggo, Penny A (2007) Cellular and clinical impact of Haploinsufficiency for genes involved in ATR signaling. American Journal of Human Genetics, 81 (1). pp. 77-86. ISSN 0002-9297

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: Gee Wheatley
Date Deposited: 17 Jul 2008
Last Modified: 03 Jul 2019 01:10
URI: http://sro.sussex.ac.uk/id/eprint/1809
Google Scholar:34 Citations

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