Xeroderma Pigmentosum

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Xeroderma Pigmentosum
Gable Sadovsky
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• Definition of Xeroderma Pigmentosum XP
• XP, first described in 1874, is a rare genetic
  defect in the nucleotide excision repair
  mechanism. It is characterized by
  hypersensitivity to the ultraviolet portion of
  sunlight.

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• Symptoms of XP
• increased skin and eye cancers
• early onset of freckling
• blistering with minimal sun exposure
• blindness and deafness
• dwarfism and hypergonadism
• mental retardation

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• Basic Statistics on XP
• XP is an autosomal recessive disease
• XP patients are 1000 times as susceptible to
  sunlight
• induced skin cancers
• About 1 person in 100,000 has the disease
• It effects both young and old, although the
  disease is
• usually diagnosed at a very early age.

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Skin Cancer Rates in XP Patients
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CANCER ETIOLOGYDNA damage causes mutations that
activate oncogenes or inactivate tumor suppressor
genes.
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Oncogenes

• Growth factor receptors
• Protein tyrosine kinases (e.g., ras and src)
• Transcription factors (e.g., Fos, Jun, Myc)

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Tumor suppressor genes

• Cell cycle control and apoptosis
• p53 (guardian of the cell)
• p21 and p16 (CDK inhibitors)
• Rb (negative regulator of E2F)
• DNA repair

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XP is characterized by an inability of a cell to
repair damage caused by UV leading to genetic
instability and skin cancer.
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Nucleotide Excision Repair or (NER) This
system is responsible for removing the damaged
segments of DNA and restoring the original
sequence of DNA. The NER mechanism is composed of
two types global genome (GGR) and transcription
coupled (TCR) Seven XP genes are central to NER
which includes many other accessory proteins.
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Complementation Groups for XP XPA XPB XPC XPD XP
E XPF XPG
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• DNA damage recognition
• XPA and XPC are both damage-recognition
  proteins and are considered the
  classical forms of XP.
• (XPE is probably also involved in damage
  recognition)

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Current Model for Mammalian NER
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• DNA damage accessibility
• XPB and XPD are topoisomerases that unwind the
  damaged region of DNA. They are components of
  the general transcription factor TFIIH. Defects
  in XPB or XPD lead to the developmental and
  neurological symptoms of XP (e.g., dwarfism,
  hypogonadism, etc.)

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Current Model for Mammalian NER
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• DNA incision enzymes
• XP-F and XP-G are responsible for making
  incisions at either side of the damage, leading
  to the release of a 29 base fragment including
  the damaged bases.

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Current Model for Mammalian NER
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• Evidence supporting UVB damage to XPA repair
  gene
• A group of scientist at the University of
  Utrecht , The Netherlands did an experiment
  involving transgenic mice in which the XPA gene
  had been knocked out.. The three groups of
  mice they studied had functional XPA (XPA
  /), were heterozygous for XPA ( XPA /-), or
  had nonfunctional XPA ( XPA -/-) .
• The purpose of the experiment was to compare the
  effects of UVB light and carcinogen exposure in
  the three different groups.

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• Effects on the Embryonic stage of development
• Problems began to develop with the XPA -/-
  genotype 13 days after conception. These
  included
• growth retardation
• decreased liver size
• embryonic anemia, resulting in a 50 mortality
  rate.
• In both XPA / and XPA/- there were no
  abnormalities observed in this stage of
  development.

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• Postnatal effects
• All three genotypes of XPA developed very
  similarly until they reached 13 months old.
• At this time primary fibroblasts were taken from
  each mouse group and exposed to 4 Jm -2 of UVB
  light.
• The XPA -/- cells had a 90 mortality rate.
• Both the XPA / and XPA /- genotypes
  suffered no losses to exposure to UVB light.
• These results are very similar to those found in
  cells isolated from XP patients.

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• UV carcinogenesis protocol
• To test the mices susceptibility to skin cancer
  all three genotypes were exposed to one (1) low
  daily dose of UVB light which gradually increased
  to 310 Jm-2 for a total of eight weeks.

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• Effects of UVB on skin cancer
• After one week of exposure to UVB light
• XPA / and XPA /- mice showed no external
  signs of exposure
• XPA -/- mice showed hyperkeratosis and
  necrosis on exposed dorsal areas of the skin

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• Effects of UVB on skin cancer
• Six weeks into the experiment the evidence of
  damage became more evident in XPA -/-.
• Abnormalities in the eyes were observed in the
  XPA-/- knockouts, but not in the normal or
  heterozygous mice.

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• Effects of UVB on skin cancer
• The UVB exposure was discontinued after 14 weeks
  due to
• the overwhelming presence of Bowenoid lesions
  found in
• the eyes of the XPA-/- mice.
• It was at this time that the first cancers were
  noticed in the
• XPA-/- mice.
• 75 of the XPA -/- mice developed at least one
• squamous cell carcinoma by week 25.
• No cancers were observed in the other two
• phenotypes

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• Experimental Results
• Mice with a defect in the XPA gene (XPA -/- ) and
  defective in NER strongly mimic the phenotype of
  XP patients. These mice have become very
  important tools for understanding the molecular
  biology of skin cancer and developing strategies
  for its prevention.

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Conclusion XP is a hidden disease that robs
its hosts of their freedom. It also is a disease
that begins to effect a person at a very young
age. Further XP research is necessary and
important if we are to eliminate this
degenerative disease.

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