Wednesday, August 27, 2014

How mutations in ERCC3 gene cause XP?

A single mutation in the ERCC3 gene causes Xeroderma Pigmentosum (XP). The mutation replaces the amino acid phenylalanine with the amino acid serine at protein position 99 (written as Phe99Ser or F99S) which greatly reduces the ability of the TFIIH complex to repair damaged DNA. As a result, abnormalities accumulate in DNA causing cells to malfunction and eventually become cancerous or die. These problems with DNA repair process cause people with XP to be extremely sensitive to UV rays from sunlight. When UV rays damage genes that control cell growth and division, cells can grow uncontrollably too fast, increasing the risk of developing cancer in XP patient. These cancers occur most frequently in areas of the body which are exposed to the sun such as the skin and eyes.

In addition to sun sensitivity, XP is sometimes associated with progressive neurological abnormalities but in affected individuals with Phe99Ser mutation have mild neurological abnormalities including hearing loss and poor coordination. Studies suggest that the neurological abnormalities associated with this condition result from a buildup of DNA damage, though the brain is not exposed to UV rays. Researchers suspect that other factors can damage DNA in nerve cells. It is unclear why some people with XP develop neurological abnormalities and others do not.

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