Ataxia-telangiectasia (A-T) is a highly pleiotropic, autosomal recessive disease that leads to multisystem defects and has an intricate cellular phenotype, all linked to the functional inactivation of a single gene. Extensive research on the phenotype and the recent discovery and cloning of the responsible gene point to a defect as a central biochemical locus which links several signal transduction pathways that operate under stress as well as in normal physiological conditions. Ataxia is the first symptom in all patients and is predominantly truncal, first manifested in swaying of the head and trunk on standing and even sitting. Truncal ataxia precedes appendicular cerebellar disease. In the first years of life, certain manifestations are present such as dysarthria, muscular hypotonia, the slow initiation and performance of all voluntary movements, characteristic hypotonic facies and postures, and drooling. Dyssynergia and intention tremor of the upper extremities become a major feature after the fifth year of life. The tendon reflexes are diminished or lost, but may be normal or even hyperactive in the early stages. All these observations show a clear ataxia of cerebellar type, initially of station and gait, and later of intention. Early observations of brains from patients with A-T showed neurodegenerative changes, particularly in the Purkinje and granular cells of the cerebellum. Neuronal degeneration is also present in the brainstem, and dentate and olivary nuclei atrophy. Neuronal loss occurs in the substantial nigra and oculomotor nuclei, dorsal root ganglia, and degenerative changes are evident in spinal motor neurons, and dorsal root and sympathetic motor neurons. Moreover, multiple abnormalities in Purkinje cell development have been observed in an Atm-deficient mouse model. Misplaced Purkinje cells have been observed in both the granular and molecular cell layers. In addition, Purkinje cell dendrites tend to grow laterally instead of extending towards the surface of the cerebellum. ATM (for Ataxia-telangiectasia mutated) has been located by restriction-fragment length polymorphism in the chromosome 11, location: 108,093,211-108,239,829. Interestingly, the site of ATM is the same or adjacent to the region occupied by CD3 (Antigen, Delta subunit), THY1 (T-Cell antigen), and NCAM (Cell Adhesion Molecule, Neural, 1) genes, all of which are members of the immunoglobulin-gene superfamily and consequently may be subject to the same defect that afflicts the T-cell receptor and immunoglobulin molecules in A-T. The ATM gene presents an open reading frame (ORF) of 9,165 kb cDNA and is constituted by 66 exons spread over 150 kb of genomic DNA which has a transcript of 12 kb. The ORF of this transcript predicts a 370-kDa protein composed of 3056 amino acids. Over 300 mutations have been found in A-T patients, distributed across the full length (150 kb of genomic DNA) of the ATM gene. Sequence homology indicates that the atm gene product falls into a family of proteins that are related to the catalytic subunit of phosphatidylinositol 3-kinase (PI 3-kinase). This family includes TEL1, MEC1, TOR1, and TOR2 of the budding yeast Saccharomyces cerevisiae, RAD3 of the fission yeast Schizosaccharomyces pombe, and MEI-41 of Drosophila melanogaster. The mammalian family member most closely related to ATM is the ATR/FRP1 protein and, like its yeast homologs, it mediates cellular responses to unreplicated or damaged DNA. In humans the PI 3-kinase family includes the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) and FRAP. These sequence homologies appear to reflect functional homology because many of the PI 3-kinase family members are involved in DNA repair, recombination and cell cycle control. Despite the resemblance to lipid kinases, members of this family, including ATM, possess a serine/threonine protein kinase activity, which is wortmannin sensitive. ATM phosphoprotein is ubiquitously expressed and predominantly found in nuclei of proliferating cells, but subcellular fractionation and immunofluorescence revealed that 10-20% of the protein is present in cytoplasmic vesicles, including peroxisomes and endosomes and a prominent cytoplasmic fraction in mouse oocytes. ATM is endosome-bound in mouse neurons, suggesting molecular sorting of the protein occurs in the cytoplasm. In Purkinje cells, distribution of ATM protein is primarily in cytoplasm, and this may be related to the differentiation state of the cells. ATM mRNA is present in all human and mouse tissues. In situ hybridization shows that ATM mRNA is expressed throughout the whole mouse embryo. Furthermore, ATM has been associated with beta-adaptin in lymphoblast vesicles indicating that it may play a role in intracellular vesicle and/or protein transport mechanisms. No obvious nuclear localization signals have been detected in ATM. Neither an ectopically expressed N-terminal fragment of the protein nor a C-terminal fragment is capable of entering the nucleus. c00 f8d ec6 f92 c47 e2a a9a a23 c1b d45 e3f fe4 d0e d3d bd3 c38 fc4 c91 f37 b43 e9a cf3 bfb caa ded f03 e12 dc4 d7a e7f a13 b67 e40 f20 baf c15 d31 ed4 cad b80 b0a c88 e65 dca dec f18 b29 ad1 d3a dfc d8e eb2 d93 ae2 ecc f9d d75 df4 be6 c96 b19 a3e c42 b9e b5d a8b ea3 b2b b59 ad2 eaa a7e c3d bd5 de4 fa9 bf0 b20 b90 d72 bad ef8 e91 cb9 ba9 eeb e88 d91 cd0 d78 b3c a88 e3b c31 cab a61 b95 b18 b12 d5e c58 def ac0 deb ee3 c00 fcc ab1 bf1 c32 ffa d5d bb2 a10 d7d a0a ac2 b7b dbb bd1 fa3 ed9 de0 c9f d2f d18 a99 ae8 fca fd0 b0d e93 d8a c61 c1d c89 e3c e83 f09 af3 ca4 e94 c86 a54 a14 de7 bb5 c7d f45 a17 a39 f0a d61 b62 e3b c31 c20 ef9 ad3 e9c f21 f2b b02 f6f df7 b94 f7e b85 c90 e40 efc b76 c01 c64 a70 de0 adb be3 e1b a6a f2f fa5 c74 bc1 be8 d9e af7 dcb f7d a60 b10 a27 dae df4 be6 c96 b19 a3e c42 df4 be6 c96 b19 a3e c42 df4 be6 c96 b19 a3e c42 c83 fc0 ede e11 da2 b21 ff4 b79 aaa b62 e3b c31 c20 ef9 ad3 c7d f45 a17 a39 f0a d61 18424430 PubMed Expanded roles for Chk1 in genome maintenance. 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