Ataxia Telangiectasia (AT)

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Ataxia Telangiectasia (AT)

• By Brandy Chapman

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Characteristics of Ataxia-telangiectasia

• Progressive neuronal degeneration
• Loss of cerebellar function
• Immunodeficiency
• Sterility
• Clinical radiation sensitivity
• Cancer predisposition

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Important Definitions

• 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

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Causes of Ataxia-telangiectasia

• Hereditary ataxia
• A 714 chromosome translocation
• Truncation of the AT gene
• Acquired ataxia related to
• Alcoholism
• Vitamin deficiencies
• Multiple sclerosis
• Vascular disease
• Primary or metastatic tumors

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Ataxia-telangiectasia is a hereditary, autosomal
recessive disease
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Diagnosis and Testing

• Genetic forms of the disease
• Family history
• Physical examination
• Neuro-imaging
• Karyotyping
• Non-genetic forms
• molecular genetic tests

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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

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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

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ATM
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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

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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

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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

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Cancers Commonly Associated with
Ataxia-Telangiectasia

• Acute Lymphocytic Leukemias and lymphomas
• Epithelial tumors
• Thymic tumors
• Breast Cancer