Cancer, neurological disorders

Ataxia; Ataxia telangiectasia; Seckel syndrome; Cutaneous telangiectasia and cancer syndrome, familial; Alpha-thalassemia X-linked intellectual disability syndrome; Alpha-thalassemia X-linked intellectual disability syndrome linked to chromosome 16; Chronic active Epstein-Barr virus infection; Primary autosomal recessive microcephalies and Seckel syndrome spectrum disorders; Jawad syndrome; Seckel syndrome Type 1; Alpha-thalassemia/mental retardation syndrome; Gapo syndrome; Seckel syndrome Type 8

Ataxia-telangiectasia (AT) is a rare neurological disease characterized by the degeneration of the cerebellum leading to uncoordinated locomotion and speech patterns as well as problems with balance and hand dexterity. Seckel syndrome is a genetic disease characterized by stunted growth, microcephaly, mental retardation, and abnormal facial features (e.g. large eyes, a beak-like nose, and a narrow face). This disease is inherited in an autosomal recessive manner. ATR is a member of the phosphatidylinositol kinase-related kinase (PIKK) family of large molecular weight kinases which have functions in cell cycle progression, DNA recombination, and detection of DNA damage. Specifically, ATR is an essential component of the DNA damage checkpoint that is critical for the detection and cellular response to DNA damage and replication stress. Loss-of-function mutations in the ATR gene result in impaired cellular detection and response to DNA damage and are associated with cell cycle abnormalities, aneuploidy, and aberrant cell growth. Several mutations in the ATR gene have been observed in patients with Seckel syndrome. For example, a synonymous single base substitution mutation (2101A-G) that resulted in the use of 2 cryptic splice sites in exon 9 of the gene resulting in premature termination and truncation of the protein, a D1879Y substitution mutation, a 540-kb deletion mutation encompassing the ATR gene, a M1159I substitution mutation at a highly conserved residue in the UME domain, and a C-to-G transversion mutation in intron 40 leading to premature termination (Val2300GlyfsTer75) of the protein. In animal studies, transgenic mice that are homozygous for the A-to-G transversion mutation in exon 9 of the ATR gene displayed severe dwarfism, microcephaly, and facial abnormalities. In addition, these mice showed reduced brain size, cyst formation, and corpus callosum agenesis, thus closely resembling the phenotype of Seckel syndrome in humans. In addition, mice heterozygous for this mutation displayed retinal and optic nerve degeneration at post-natal day 20 (P20) despite normal embryonic development, and possessed cilia that were ~40% shorter than those in wild-type mice. Therefore, loss-of-function of the ATR gene may play a role in the the pathology of ataxia-telangiectasia and Seckel syndrome.
 

Hemangiomas, capillary infantile

ATR appears to be a tumour suppressor protein (TSP). Cancer-related mutations in human tumours point to a loss of function of the protein kinase. The active form of the protein kinase normally acts to inhibit tumour cell proliferation. ATR levels are up-regulated 1.6-fold in human tumours compared to most other protein kinases. Loss-of-function mutations in ATR, which abolish the DNA damage detection ability of the protein, have been linked to hemangioma, a cancer that develops in the endothelial cells that line blood vessels of the cardiovascular system. Somatic mutations in the ATR gene are rarely observed in human cancer specimens, with the possible exception of sporadic stomach and endometrial cancers that display microsatellite instability. In animal studies, mice heterozygous for a loss-of-function mutation in the ATR gene exhibit similar survival times as wild-type mice, but have an increased occurence of tumour formation, which supports a role for the protein in the prevention of tumorigenesis. Caffeine is an inhibitor of ATR. Interestingly, caffeine exposure is known to sensitize tumours to ionizing radiation and other toxic agents, which is associated with the disruption of cell-cycle checkpoints.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Barrett's esophagus epithelial metaplasia (%CFC= +69, p<0.045); Bladder carcinomas (%CFC= +169, p<0.0004); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= -67, p<0.0004); Colon mucosal cell adenomas (%CFC= +55, p<0.003); Malignant pleural mesotheliomas (MPM) tumours (%CFC= +89, p<0.045); Oral squamous cell carcinomas (OSCC) (%CFC= +103, p<0.0001); and Skin melanomas - malignant (%CFC= -47, p<0.022). The COSMIC website notes an up-regulated expression score for ATR in diverse human cancers of 746, which is 1.6-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 123 for this protein kinase in human cancers was 2.1-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.06 % in 25343 diverse cancer specimens. This rate is only -19 % lower than the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.31 % in 1128 large intestine cancers tested; 0.25 % in 807 skin cancers tested; 0.18 % in 602 endometrium cancers tested; 0.16 % in 590 stomach cancers tested; 0.09 % in 1813 lung cancers tested; 0.07 % in 605 oesophagus cancers tested; 0.07 % in 1270 liver cancers tested; 0.05 % in 1380 breast cancers tested.

Most frequent mutations with the number of reports indicated in brackets: R256C (4).

Only 4 deletions, 3 insertions, and 2 complex mutations are noted on the COSMIC website.