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Ataxia Telangiectasia (AT)

Ataxia Telangiectasia (AT). By Brandy Chapman. Characteristics of Ataxia-telangiectasia:. Progressive neuronal degeneration Loss of cerebellar function Immunodeficiency Sterility Clinical radiation sensitivity Cancer predisposition.

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Ataxia Telangiectasia (AT)

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  1. Ataxia Telangiectasia (AT) By Brandy Chapman

  2. Characteristics of Ataxia-telangiectasia: • Progressive neuronal degeneration • Loss of cerebellar function • Immunodeficiency • Sterility • Clinical radiation sensitivity • Cancer predisposition

  3. Ataxia: poor coordination of movement, including wide-based, uncoordinated, unsteady gait Associated with dysfunction of the cerebellum Telangiectasia: dilation of small blood vessels and capillaries usually of the sclera, face, and ears Important Definitions

  4. Causes of Ataxia-telangiectasia • Hereditary ataxia • A 7;14 chromosome translocation • Truncation of the AT gene • Acquired ataxia related to • Alcoholism • Vitamin deficiencies • Multiple sclerosis • Vascular disease • Primary or metastatic tumors

  5. Ataxia-telangiectasia is a hereditary, autosomal recessive disease

  6. Diagnosis and Testing • Genetic forms of the disease: • Family history • Physical examination • Neuro-imaging • Karyotyping Non-genetic forms: molecular genetic tests

  7. About AT….. • A childhood disorder, generally detected between the ages 1-4 • Atrophy of the cerebellum, generally death by mid twenties • Heterozygotes are asymptomatic • Prenatal testing is available

  8. Molecular Biology of AT • AT is due to loss of function of the AT gene encoding the ATM protein • The ATM protein is a master regulator in a DNA damage response cycle or checkpoint • ATM • Location: Chromosome 11, q22 • A nuclear protein with a PI-3 K domain(phosphatidylinositol 3-kinase) on the carboxy terminus

  9. ATM

  10. Normal function of ATM • A high molecular weight serine/threonine protein kinase with a PI-3 domain necessary for proper response to Double Stranded DNA Breakage • Related to MEC1/ERS1 in S. cerevisiae, Rad3 in S. pombe and Mei-41 in Drosophilae • Present in all cells with higher expression in the testis, spleen, and thymus • Possibly activated by C1D, which responds to DNA breaks, via the leucine zipper motif • Requires presence of Mn2+ for function

  11. ATM Function in Cell Cycle Checkpoints • DNA DS break  ATM p53 at serine 15 • Ser15 controls the binding of p53 to mdm2 • Mdm2: 1. inhibits transactivation by p53 2. targets p53 for proteolytic degradation when bound • Phosphorylation of ser15 stabilizes p53 by limiting its ability to bind to mdm2 • ATM may also activate a p53-specific phosphatase, dephosphorylating ser 376, promoting enhanced DNA binding activity

  12. ATM Deficiency Contributes to Cancer • Without ATM, p53 is not activated in response to DS DNA breaks and the cell fails to arrest in G1 or undergo apoptosis • Loss of ATM leads to • Increased frequency of spontaneous chromosome rearrangement and telomeric fusions • Accelerated telomere shortening • Increased rates of intra- and extra-homologous recombination events • Increased numbers of chromosome gaps and breaks • Radiosensitivity and IR-induced chromosome instability

  13. Cancers Commonly Associated with Ataxia-Telangiectasia • Acute Lymphocytic Leukemias and lymphomas • Epithelial tumors • Thymic tumors • Breast Cancer

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