Localization of an ataxia-telangiectasia gene to chromosome 11q22–23

Abstract

Ataxia-telangiectasia (AT) is a human autosomal recessive disorder of childhood characterized by: (1) progressive cerebellar ataxia with degeneration of Purkinje cells; (2) hypersensitivity of fibroblasts and lymphocytes to ionizing radiation; (3) a 61-fold and 184-fold increased cancer incidence in white and black patients, respectively; (4) non-random chromosomal rearrangements in lymphocytes; (5) thymic hypoplasia with cellular and humoral (IgA and IgG2) immunodeficiencies; (6) elevated serum level of alphafetoprotein; (7) premature ageing; and (8) endocrine disorders, such as insulin-resistant diabetes mellitus. A DNA processing or repair protein is the suspected common denominator in this pathology. Heterozygotes are generally healthy; however, the sensitivity of their cultured cells to ionizing radiation is intermediate between normal individuals and that of affected homozygotes. Furthermore, heterozygous females are at an increased risk of breast cancer. These findings, when coupled with an estimated carrier frequency of 0.5-5.0%, suggest that (1) as many as one in five women with breast cancer may carry the AT gene and that (2) the increased radiation sensitivity of AT heterozygotes may be causing radiation therapists to reduce the doses of radiation used for treating cancer in all patients. To identify the genetic defect responsible for this multifaceted disorder, and to provide effective carrier detection, we performed a genetic linkage analysis of 31 families with AT-affected members. This has allowed us to localize a gene for AT to chromosomal region 11q22-23.

An early-onset recessive cerebellar disorder with distal amyotrophy and, in two patients, gross myclonia: a probable ataxia telangiectasia variant

“…An AT locus (or loci) has been assigned to chromosome 1 lq22-23 [32][33][34]. Complementation studies after mutual fusion of cells from different patients have demonstrated the existence of 4 different AT complementation groups and 2 groups for the related Nijmegen breakage syndrome [35].…”

ATM and breast cancer susceptibility

“…The gene for ataxia-telangiectasia was mapped to chromosome 11q by genetic linkage analysis in 1988 and was identified by positional cloning in 1995 (Gatti et al, 1988;Savitsky et al, 1995). The gene was called ATM (ataxia-telangiectasia mutated).…”

An anti-sense construct of full-length ATM cDNA imposes a radiosensitive phenotype on normal cells

“…The A-T gene was initially mapped to chromosome 11q22-23 by Gatti et al (1988) and more recently isolated by positional cloning (Savitsky et al, 1995a). This gene, ATM, occupies 150 kb of genomic DNA and codes for a 13 kb mRNA with an open reading frame of 9.165 kb (Savitsky et al, 1995b;Uziel et al, 1996).…”