ATM Mutations and Phenotypes in Ataxia-Telangiectasia Families in the British Isles: Expression of Mutant ATM and the Risk of Leukemia, Lymphoma, and.

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ATM Mutations and Phenotypes in Ataxia-Telangiectasia Families in the British Isles: Expression of Mutant ATM and the Risk of Leukemia, Lymphoma, and Breast Cancer T. Stankovic, A.M.J. Kidd, A. Sutcliffe, G.M. McGuire, P. Robinson, P. Weber, T. Bedenham, A.R. Bradwell, D.F. Easton, G.G. Lennox, N. Haites, P.J. Byrd, A.M.R. Taylor The American Journal of Human Genetics Volume 62, Issue 2, Pages 334-345 (February 1998) DOI: 10.1086/301706 Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of families 46 and 109. Arrows indicate family members with breast cancer, whose ages are also given. In family 109 the affected patient 109 II-5 has a son. In family 46, the two A-T patients 46 II-1 and 46 II-2 each carry a 7271T→G and 3910del7nt ATM mutation indicated by a filled in and hatched symbol respectively. There were 3 miscarriages in this family. The American Journal of Human Genetics 1998 62, 334-345DOI: (10.1086/301706) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 2 Western blot showing presence or absence of ATM expression in LCLs from A-T patients. Lanes 1 and 20, Extracts from two different normal LCLs showing a 350-kD band corresponding to the ATM protein of normal size. Lanes 2–19, Extracts from A-T LCLs with the patient designation given above the lanes (these are the same as given in table 4). Lanes 2–4, LCLs from patients with T-PLL or clonal proliferation. Lanes 5–12, LCLs from patients with T-cell tumors. Lanes 13 and 14, LCLs from patients with T-cell proliferation. Lanes 15–17, LCLs from patients with B-cell tumors. Lane 18, Acute myeloid leukemia. Lane 19, LCL from a patient with Hodgkins lymphoma. Lanes 2, 5–10, 13, 15, and 18, Varying levels of ATM protein, particularly low in samples in lanes 10 and 13. Lanes 3, 4, 11, 12, 14, and 19, Absence of any protein. The American Journal of Human Genetics 1998 62, 334-345DOI: (10.1086/301706) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 3 A, SSCP analysis of 185-bp RT-PCR fragment digested with restriction enzymes ApoI or AluI for specific identification of the mutation common to individuals in families 109 and 46. The arrows point to a mobility shift in each digest, which is associated with the mutant allele. Lanes 1–4, Mother (109 I-2; heterozygous for the 7271T→G mutation) and the three affected siblings (109 II-1, 109 II-5, and 109 II-6, respectively, all of whom are homozygous for this mutation), from family 109. Lanes 5–8, Mother (46 I-6; not a carrier of the 7271T→G mutation), father (46 I-5; heterozygous for the 7271T→G mutation), and the two affected siblings (46 II-1 and 46 II-2; both of whom are heterozygous for the mutation). Lane 9, Normal control. B, Western blot analysis of LCLs derived from members of families 46 and 109, by use of ATM antibody FP8. Lanes 1 and 12, Extract of LCL from a normal individual, showing 350-kD band corresponding to the ATM protein of normal size. Lanes 2 and 11, Negative control from A-T patient 28-3, showing absence of ATM protein, as a result of mutations causing truncation of the protein from both alleles. Lanes 3-6, Mother (109 I-2; heterozygous for the 7271T→G mutation), showing presence of ATM protein of normal size, and the three affected siblings (109 II-1, 109 II-5, and 109 II-6, respectively; all of whom are homozygous for this mutation), also showing the normal size and levels of ATM protein. Lanes 7–10, Mother (46 I-6; not a carrier of the 7271T→G mutation), father (46 I-5; heterozygous for the 7271T→G mutation), and the two affected siblings (46 II-1 and 46 II-2; both of whom are heterozygous for the mutation), all showing presence of normal-size ATM protein but at lower levels in the affected siblings. The American Journal of Human Genetics 1998 62, 334-345DOI: (10.1086/301706) Copyright © 1998 The American Society of Human Genetics Terms and Conditions