title: Germline mutation in ATR in autosomal- dominant oropharyngeal cancer syndrome.
abstract: ATR (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.
authors.affiliation: St. John's Institute of Dermatology, King's College London, Guy's Campus, London, UK.
authors.forename: Akio
authors.initials: A
authors.lastname: Tanaka
authors.forename: Sarah
authors.initials: S
authors.lastname: Weinel
authors.forename: Nikoletta
authors.initials: N
authors.lastname: Nagy
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.forename: Joey E
authors.initials: JE
authors.lastname: Lai-Cheong
authors.forename: Carol L
authors.initials: CL
authors.lastname: Kulp-Shorten
authors.forename: Alfred
authors.initials: A
authors.lastname: Knable
authors.forename: Gillian
authors.initials: G
authors.lastname: Carpenter
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Fisher
authors.forename: Makiko
authors.initials: M
authors.lastname: Hiragun
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Yanase
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hide
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Callen
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D025063:Chromosome Disorders / Q000235:genetics*; D002875:Chromosomes; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D016158:Genes, p53 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009959:Oropharyngeal Neoplasms / Q000235:genetics*; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases