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Akio Tanaka, Sarah Weinel, Nikoletta Nagy, Mark O'Driscoll, Joey E

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Presentation on theme: "Akio Tanaka, Sarah Weinel, Nikoletta Nagy, Mark O'Driscoll, Joey E"— Presentation transcript:

1 Germline Mutation in ATR in Autosomal- Dominant Oropharyngeal Cancer Syndrome 
Akio Tanaka, Sarah Weinel, Nikoletta Nagy, Mark 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. McGrath  The American Journal of Human Genetics  Volume 90, Issue 3, Pages (March 2012) DOI: /j.ajhg Copyright © 2012 The American Society of Human Genetics Terms and Conditions

2 Figure 1 Pedigree, Linkage Analysis, and Clinicopathological Features of This Autosomal-Dominant Disorder Associated with a Missense Mutation in ATR (A) The family pedigree. Squares denote male family members, and circles denote female family members. A 17.3 Mb critical region is defined by recombination events in individual IV:6 for rs and in individuals IV:3 and IV:12 for SNP rs (B, C, and D) Carriers are a 6-year-old female (B), a 35-year-old female (C), and a 56-year-old male (D) with telangiectases on the face as well as thin outer eyebrows. (E) A 25-year old female carrier with the additional feature of a papillomatous tumor in the upper-pharynx (tonsillar) region with histological features of squamous cell carcinoma. (F and G) Histopathological feature of squamous cell carcinoma in the upper pharynx (tonsillar) region of affected individual IV-12. The epidermis shows full-thickness dysplasia with hyperkeratosis and parakeratosis (hematoxylin and eosin stain; original magnification is ×100) (F). Nests of carcinoma cells are infiltrating into the submucosal tissue (hematoxylin and eosin stain; original magnification is ×200) (G). Additional pedigree data are detailed in Table S1 and S2. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

3 Figure 2 Genome-Wide Linkage Analysis
(A) Genome-wide parametric linkage analysis reveals a LOD score of >2.5 on chromosome 3. (B) Magnification of the LOD-score diagram of the chromosome 3 region. The chromosome 3 peak extends from SNP rs to rs (116–155 cM), and the max LOD is 2.7. Fine mapping with microsatellite markers and SNP array data (Figure 1A) narrowed the candidate region to a ∼16.8 cM interval in region 3q22–24 between rs and rs (C) This interval contains ∼90 genes, including ATR. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

4 Figure 3 Identification of a Pathogenic Mutation in ATR
(A) Nucleotide sequencing of genomic DNA extracted from the blood of an affected individual reveals a heterozygous missense mutation, c.6431A>G (p.Gln2144Arg), in ATR (“affected blood”) but a homozygous or hemizygous mutation in an oropharyngeal-cancer lesion (“affected OPC”) from carrier individual IV-12. (B) Analysis of the mutation c.6431A>G in ATR with restriction enzyme MfeI. PCR products from the wild-type (“Wt”) allele were digested, whereas those from the mutant (“Mt”) allele were not. Control-blood DNA shows only a digested band (“control blood”). DNA extracted from blood shows both an undigested band and a digested band (“IV-12 blood”) but only an undigested band from the oropharyngeal-cancer lesion (“IV-12 OPC”) in carrier individual IV-12. (C) A schematic representation of ATR (NP_ ). The mutation occurs within the FAT domain of ATR. The substituted amino acid (p.Gln2144) is well conserved throughout various evolutionary lineages. (D) Immunoblot of ATR in fibroblast extracts. “NF” indicates control fibroblasts from a healthy donor; “F04-12” and “F04-20” are fibroblasts from carriers IV-12 and IV-20, respectively, in Figure 1A; “ATR-S” denotes fibroblasts derived from an individual with ATR Seckel syndrome; MCM2 (minichromosome maintenance complex component 2) was used as a loading control. The antibodies sc-1887 (for ATR) and sc-9839 (for MCM2) were purchased from Santa Cruz (Santa Cruz, CA). (E) Immunoblot of p53 in fibroblast extracts (of both carriers and controls) before and after the activation of ATR by hydroxyurea (“HU”) exposure for two hours; β-actin was used as a loading control. The antibodies #9282 (for p53) and #4967 (for β-actin) were purchased from Cell Signaling (Beverly, MA). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

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