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: Mark O'Driscoll, William B Dobyns, Johanna M van Hagen, Penny A Jeggo
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 81 Issue 1 Pg. 77-86 (Jul 2007) ISSN: 0002-9297 [Print] United States
• PMID: 17564965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• RFC2 protein, human
• RNA, Small Interfering
• RPA1 protein, human
• Replication Protein A
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• Protein Serine-Threonine Kinases
• Replication Protein C

Topics

• Ataxia Telangiectasia (genetics)
• Ataxia Telangiectasia Mutated Proteins
• 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)