| Cellular and clinical impact of haploinsufficiency for genes involved in ATR signaling. | |
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MedLine Citation:
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PMID: 17564965 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Mark O'Driscoll; William B Dobyns; Johanna M van Hagen; Penny A Jeggo |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-05-17 |
Journal Detail:
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Title: American journal of human genetics Volume: 81 ISSN: 0002-9297 ISO Abbreviation: Am. J. Hum. Genet. Publication Date: 2007 Jul |
Date Detail:
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Created Date: 2007-06-13 Completed Date: 2007-09-04 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 0370475 Medline TA: Am J Hum Genet Country: United States |
Other Details:
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Languages: eng Pagination: 77-86 Citation Subset: IM |
Affiliation:
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Genome Damage and Stability Centre, University of Sussex, Brighton, UK. m.o-driscoll@sussex.ac.uk |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Ataxia Telangiectasia
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genetics Blepharophimosis / genetics Blepharoptosis / genetics Cell Cycle Proteins / genetics* Cell Line Chromosomes, Human, Pair 7 / genetics DNA Damage / genetics* Dwarfism / genetics* Gene Deletion Haploidy* Humans Microcephaly / genetics* Protein-Serine-Threonine Kinases / genetics* RNA, Small Interfering / pharmacology Replication Protein A / genetics Replication Protein C / genetics Signal Transduction / genetics Syndrome Williams Syndrome / genetics |
| Chemical | |
Reg. No./Substance:
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0/Cell Cycle Proteins; 0/RFC2 protein, human; 0/RNA, Small Interfering; 0/RPA1 protein, human; 0/Replication Protein A; 0/Replication Protein C; EC 2.7.1.-/ATR protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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