File(s) under permanent embargo
Germline Mutation in ATR in Autosomal- Dominant Oropharyngeal Cancer Syndrome
journal contribution
posted on 2023-06-08, 11:15 authored by Akio Tanaka, Sarah Weinel, Nikoletta Nagy, Mark O'DriscollMark O'Driscoll, Joey E Lai-Cheong, Carol L Kulp-Shorten, Alfred Knable, Gillian Carpenter, Sheila A Fisher, Makiko Hiragun, Yuhki Yanase, Michihiro Hide, Jeffrey Callen, John A McGrathATR (ataxia telangiectasia and Rad3 related) is an essential regulator of genome integrity. It controls and coordinates DNA-replication origin firing, replication-fork stability, cell-cycle checkpoints, and DNA repair. Previously, autosomal-recessive loss-of-function mutations in ATR have been demonstrated in Seckel syndrome, a developmental disorder. Here, however, we report on a different kind of genetic disorder that is due to functionally compromised ATR activity, which translates into an autosomal-dominant inherited disease. The condition affects 24 individuals in a five-generation pedigree and comprises oropharyngeal cancer, skin telangiectases, and mild developmental anomalies of the hair, teeth, and nails. We mapped the disorder to a ~16.8 cM interval in chromosomal region 3q22–24, and by sequencing candidate genes, we found that ATR contained a heterozygous missense mutation (c.6431A>G [p.Gln2144Arg]) that segregated with the disease. The mutation occurs within the FAT (FRAP, ATM, and TRRAP) domain—which can activate p53—of ATR. The mutation did not lead to a reduction in ATR expression, but cultured fibroblasts showed lower p53 levels after activation of ATR with hydroxyurea than did normal control fibroblasts. Moreover, loss of heterozygosity for the ATR locus was noted in oropharyngeal-tumor tissue. Collectively, the clinicopathological and molecular findings point to a cancer syndrome and provide evidence implicating a germline mutation in ATR and susceptibility to malignancy in humans.
History
Publication status
- Published
File Version
- Published version
Journal
American Journal of Human GeneticsISSN
0002-9297Publisher
Cell PressExternal DOI
Issue
3Volume
90Page range
511-517Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2012-04-19First Compliant Deposit (FCD) Date
2012-03-13Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC