Dataset Information


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.

SUBMITTER: O'Driscoll M 

PROVIDER: S-EPMC1950915 | BioStudies | 2007-01-01

REPOSITORIES: biostudies

Similar Datasets

2012-01-01 | S-EPMC3493446 | BioStudies
2019-02-28 | GSE121384 | GEO
1000-01-01 | S-EPMC544916 | BioStudies
2009-01-01 | S-EPMC2712957 | BioStudies
1000-01-01 | S-EPMC3343649 | BioStudies
2011-01-01 | S-EPMC3188555 | BioStudies
2008-01-01 | S-EPMC2920183 | BioStudies
2016-01-01 | S-EPMC4805311 | BioStudies
2008-01-01 | S-EPMC2397541 | BioStudies
2014-01-01 | S-EPMC4078132 | BioStudies