Sequence 207 (ATM-1 , ATM1)

Sequence ATM-1 , ATM1
Target	ATM ( Homo sapiens )
Description	Ataxia telangiectasia mutated Ensembl: ENSG00000149311 UniGene: Hs.367437 EntrezGene: 472 Ensembl Chr11: 107598769 - 107745036 Strand: 1 GO terms: 0000077 0001756 0003677 0004674 0005634 0005819 0006281 0006468 0007049 0007094 0007131 0007165 0007292 0007420 0007507 0008630 0010212 0016303 0016740 0016773 0031410 0045786 0047485
Design	siRNA
Chemistry	RNA
Sequence	siRNA sense (19b) CATCTAGATCGGCATTCAG / siRNA antisense (19b) CTGAATGCCGATCTAGATG
Application	gene silencing
Name	ATM-1 , ATM1

References

ATM-dependent CHK2 activation induced by anticancer agent, irofulven.Wang J, Wiltshire T, Wang Y, Mikell C, Burks J, Cunningham C, Van Laar ES, Waters SJ, Reed E, Wang W.J Biol Chem. 2004 Sep 17;279(38) :39584-92. Epub 2004 Jul 20.

Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Hache M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, Bishop KM. J Child Neurol. 2016 Jun;31(7):899-906. PubMed:26823478

Background

Description. Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene. Clinical Features. Homozygotes Patients present in early childhood with progressive cerebellar ataxia and later develop conjunctival telangiectases, other progressive neurologic degeneration, sinopulmonary infection, and malignancies. Telangiectases typically develop between 3 and 5 years of age. The earlier ataxia can be misdiagnosed as ataxic cerebral palsy before the appearance of oculocutaneous telangiectases. Gatti et al. (1991) contended that oculocutaneous telangiectases eventually occur in all patients, while Maserati et al. (1988) wrote that patients without telangiectases are not uncommon. A characteristic oculomotor apraxia, i.e., difficulty in the initiation of voluntary eye movements, frequently precedes the development of telangiectases.

Gonadal dysfunction in ataxia-telangiectasia was discussed by Miller and Chatten (1967), Zadik et al. (1978), and others. Thibaut et al. (1994) reviewed cases of necrobiosis lipoidica in association with ataxia-telangiectasia.

According to Boder (1985), the oldest known AT patients were a man who died in November 1978 at age 52 years and his sister who died in July 1979 at the age of almost 49 years. The sister was the subject of the report by Saxon et al. (1979) on T-cell leukemia in AT. The possibility of heteroalleles at the ataxia-telangiectasia loci might be suggested.

Animal Model. Barlow et al. (1996) created a murine model of ataxia-telangiectasia by disrupting the Atm locus via gene targeting. Mice homozygous for the disrupted Atm allele displayed growth retardation, neurologic dysfunction, male and female infertility secondary to the absence of mature gametes, defects in T lymphocyte maturation, and extreme sensitivity to gamma-irradiation. Most of the animals developed malignant thymic lymphomas between 2 and 4 months of age. Several chromosomal anomalies were detected in one of these tumors. Fibroblasts from these mice grew slowly and exhibited abnormal radiation-induced G1 checkpoint function. Atm-disrupted mice recapitulated the ataxia-telangiectasia phenotype in humans. The authors noted that humans also show incomplete sexual maturation in ATM (Boder, 1975).

Elson et al. (1996) generated a mouse model for ataxia-telangiectasia using gene targeting to generate mice that did not express the Atm protein. Atm-deficient mice were retarded in growth, did not produce mature sperm, and exhibited severe defects in T-cell maturation while going on to develop thymomas. Atm-deficient fibroblasts grew poorly in culture and displayed a high level of double-stranded chromosome breaks. Atm-deficient thymocytes underwent spontaneous apoptosis in vitro significantly more often than controls. Atm-deficient mice then exhibited many of the same symptoms found in ataxia-telangiectasia patients and in cells derived from them. Furthermore, Elson et al. (1996) demonstrated that the Atm protein exists as 2 discrete molecular species, and that loss of 1 or both of these can lead to the development of the disease.

Xu and Baltimore (1996) disrupted the mouse ATM gene by homologous recombination. Xu et al. (1996) reported that Atm -/- mice are viable, growth-retarded, and infertile. The infertility results from meiotic failure, as meiosis is arrested at the zygotene/pachytene stage of prophase I as a result of abnormal chromosomal synapsis and subsequent chromosome fragmentation. The cerebella of Atm -/- mice appear normal by histologic examination, and the mice have no gross behavioral abnormalities. Atm -/- mice exhibit multiple immune defects similar to those of AT patients, and most develop thymic lymphomas at 3 to 4 months of age and die of the tumors by 4 months. Xu and Baltimore (1996) showed that mouse Atm -/- cells are hypersensitive to gamma irradiation and defective in cell cycle arrest following radiation, and Atm -/- thymocytes are more resistant to apoptosis induced by gamma radiation than normal thymocytes. They also provide direct evidence that ATM acts as an upregulator of p53.

Ataxia-telangiectasia is characterized by markedly increased sensitivity to ionizing radiation. Ionizing radiation oxidizes macromolecules and causes tissue damage through the generation of reactive oxygen species (ROS). Barlow et al. (1999) therefore hypothesized that AT is due to oxidative damage resulting from loss of function of the ATM gene product. To assess this hypothesis, they employed an animal model of AT, i.e., the mouse with a disrupted Atm gene. They showed that organs that develop pathologic changes in the Atm-deficient mice are targets of oxidative damage, and that cerebellar Purkinje cells are particularly affected. They suggested that these observations provide a mechanistic basis for the AT phenotype and lay a rational foundation for therapeutic intervention. Barlow et al. (1999) exposed Atm +/+ and Atm +/- littermates to a sublethal dose, 4 Gy (400 Rad) of ionizing radiation. The Atm +/- mice had premature graying and decreased life expectancy (median survival 99 weeks vs 71 weeks in wildtype and heterozygous mice, respectively, P = 0.0042). Tumors and infections of similar type were found in all autopsied animals, regardless of genotype.

Worgul et al. (2002) noted that in vitro studies have shown that cells from individuals homozygous for AT are much more radiosensitive than cells from unaffected individuals. Although cells heterozygous for the ATM gene may be slightly more radiosensitive in vitro, it remained to be determined whether their greater susceptibility translated into an increased sensitivity for late effects in vivo, although there was a suggestion that radiotherapy patients heterozygous for the ATM gene may be more at risk of developing late normal tissue damage. Worgul et al. (2002) chose cataract formation in the lens as a means of assaying the effects of ATM deficiency in a late-responding tissue. One eye each of wildtype, Atm heterozygous, and Atm homozygous knockout mice was exposed to various levels of x-rays. Cataract development in the mice of all 3 groups was strongly dependent on dose. The lenses of homozygous mice were the first to opacify at any given dose. Cataracts appeared earlier in heterozygous versus wildtype mice. The data suggested that ATM heterozygotes in the human population may also be radiosensitive. Worgul et al. (2002) proposed that this information may influence the choice of individuals destined to be exposed to higher than normal doses of radiation, such as astronauts, and may also suggest that radiotherapy patients who are ATM heterozygotes could be predisposed to increased late normal tissue damage.