A gene, ATM, that is mutated in the autosomal recessive disorder ataxia telangiectasia (AT) was identified by positional cloning on chromosome 11q22-23. AT is characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities. The disease is genetically heterogeneous, with four complementation groups that have been suspected to represent different genes. ATM, which has a transcript of 12 kilobases, was found to be mutated in AT patients from all complementation groups, indicating that it is probably the sole gene responsible for this disorder. A partial ATM complementary DNA clone of 5.9 kilobases encoded a putative protein that is similar to several yeast and mammalian phosphatidylinositol-3' kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control. The discovery of ATM should enhance understanding of AT and related syndromes and may allow the identification of AT heterozygotes, who are at increased risk of cancer.

https://science.sciencemag.org/content/sci/268/5218/1749.full.pdf

A single ataxia telangiectasia gene with a product similar to pi-3 kinase

Polygenic disease: methods for mapping complex disease traits

Progression through the eukaryotic cell cycle requires the activation of cyclin-dependent kinases (CDKs). The activities of these kinases are tightly regulated by both positive and negative factors in normal cells, and perturbation of CDK activities can result in tumorigenesis (Hunter and Pines 1994; Sherr 1996). Although the regulation of CDK activation has been studied intensively in recent years, the mechanisms by which these CDKs regulate cell cycle progression are not fully understood partly because few substrates of these kinases have been identified.

Previous studies have shown that some protein kinases, including CDKs, form stable complexes with their respective substrates in vivo (Kato et al. 1993; Dynlacht et al. 1994, 1997; Krek et al. 1994; Karin and Hunter 1995; Zhu et al. 1995; Adams et al. 1996; Kallunki et al. 1996). This physical interaction has been suggested as a mechanism by which the specificity and efficiency of the kinase reactions are achieved. Thus, a possible approach for identifying substrates of a protein kinase is to search for proteins that interact physically with the kinase. We have developed a method to screen expression libraries for potential CDK substrates and identified a novel substrate of cyclin E–CDK2, a kinase complex that regulates the G1/S-phase transition and is required for the initiation of DNA replication in higher eukaryotes (Fang and Newport 1991; Ohtsubo and Roberts 1993; Tsai et al. 1993; Resnitzky et al. 1994).

/pdf/expression-of-npat-a-novel-substrate-of-cyclin-e-cdk2-5yyr1o45kv.pdf

Expression of NPAT, a novel substrate of cyclin E–CDK2, promotes S-phase entry

Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions

The ataxia-telangiectasia mutated (ATM) gene, which is mutated in the autosomal recessive disorder ataxia-telangiectasia (AT), was isolated in 1995 by positional cloning. Although in vitro cell fusion studies had suggested that AT was genetically heterogeneous, all AT patients studied to date have been found to harbor mutations in the ATM gene. More that 100 ATM mutations occurring in AT patients have been documented. The mutations are broadly distributed throughout the ATM gene. Except for patients from families with known consanguinity, most AT patients are compound heterozygotes. The majority (> 70%) of mutations are predicted to lead to protein truncation. A significant number of the reported mutations affect mRNA splicing with at least half of the coding exons (32/62) having been observed to undergo exon skipping. The large size of the ATM gene, 66 exons spanning approximately 150 kb of genomic DNA, together with the diversity and broad distribution of mutations in AT patients greatly limits the utility of direct mutation screening as a diagnostic tool, or method of carrier identification, except where founder effect mutations are involved.

Diversity of ATM gene mutations detected in patients with ataxia‐telangiectasia

In an effort to localize a gene for ataxia-telangiectasia (A-T), we have genotyped 27 affected Costa Rican families, with 13 markers, in the chromosome 11q22-23 region. Significant linkage disequilibrium was detected for 9/13 markers between D11S1816 and D11S1391. Recombination events observed in these pedigrees places A-T between D11S1819 and D11S1960. One ancestral haplotype is common to 24/54 affected chromosomes and roughly two-thirds of the families. Inferred (ancestral) recombination events involving this common haplotype in earlier generations suggest that A-T is distal to D11S384 and proximal to D11S1960. Several other common haplotypes were identified, consistent with multiple mutations in a single gene. When considered together with all other evidence, this study further sublocalizes the major A-T locus to ≈200 kb, between markers S384 and S535.

Sublocalization of an ataxia-telangiectasia gene distal to D11S384 by ancestral haplotyping in Costa Rican families.

Using a magnetic beads-mediated cDNA selection procedure and a fetal brain expression library, we identified a transcriptional unit within a cosmid positive for the marker D11S384. Pursuit of its full-length cDNA led to the cloning of the third candidate gene (CAND3) we studied in our quest for the ataxiatelangiectasia (A-T) gene, ATM. CAND3 spans ~140 kb of genomic DNA and is located immediately centrimeric to ATM, with 544 bp of DNA separating the two genes. CAND3 encodes two ubiquitously expressed transcripts of ~5.8 kb and ~4.6 kb that are divergently transcribed from a promoter region common to ATM. Nucleotide sequence was determined for one of its alternately spliced transcripts. The predicted protein has 1175 amino acids and is novel in sequence, with only weak homologies to transcriptional factors, nucleoporin protein, and protein kinases, including members of the phosphatidylinositol 3-kinase (PI-3 kinase) family. Although neither homology to ATM nor any mutation of CAND3 in A-T patients has been found, the head-to-head arrangement of CAND3 and ATM, with expression of both housekeeping genes from a common stretch of 544 bp intergenic DNA, suggests a bi-directional promoter possibly for co-regulation of biologically related functions. YACs, BACs, cosmids, and STSs are defined to aid in the further study of this gene.

CAND3: A ubiquitously expressed gene immediately adjacent and in opposite transcriptional orientation to the ATM gene at 1lq23.1.

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Sublocalization of an ataxia-telangiectasia gene distal to D11S384 by ancestral haplotyping in Costa Rican families.

CAND3: A ubiquitously expressed gene immediately adjacent and in opposite transcriptional orientation to the ATM gene at 1lq23.1.