A 6-month-old male infant from a consanguineous marriage presents with severe sunburns and freckling in sun exposed areas. The mother explains that the infant experiences these sunburns every time the infant goes outside despite applying copious amounts of sunscreen. Which of the following DNA repair mechanisms is defective in this child?
1.Nucleotide excision repair
2.Base excision repair
5.Non homologous end joining
Based on the presentation of sunburns and freckling in sun exposed areas, the child most likely has xeroderma pigmentosum (XP), which is due to a defective nucleotide excision repair.
Nucleotide excision repair is involved in removing thymidine dimers caused by UV-B light and bases damaged by chemicals. The process of removing a base occurs in several steps. The proteins XPC (xeroderma pigmentosum complementation group C) and XPB-G are involved in recognizing the DNA lesion and excising it. DNA polymerase then fills the gap followed by DNA ligase sealing the nick. Another repair process occurs during transcription when RNA polymerase stalls at the DNA lesion. The proteins CSB, XPG, and CAS recognize the stalled polymerase and remove the segment. DNA polymerase and ligase then fill in the segment allowing for transcription to continue. A lack of any of these enzymes XPA-XPG results in XP because these individuals cannot repair UV damaged DNA.
Kraemer and DiGiovanna review XP. Symptoms include sun sensitivity as exhibited by severe sunburns in about 60% of individuals with XP and freckle-like pigmentation of the face before 2 years of age. Ocular issues such as keratitis, atrophy of the epithelium of the eyelids, and photophobia are common. Some individuals (~25%) exhibit neurologic symptoms such as absent DTRs, sensorineural hearing loss, acquired microcephaly (ventricles enlarge, the cortex thins, and the skull bones thicken), and cognitive impairment. Individuals with XP have a very high risk of developing basal and squamous cell carcinoma and melanoma.
Kraemer and DioGiovanna discuss the testing of XP which is based on symptoms (skin, eye, and neurological) and family history. Laboratory tests involve screening cells for the ability to repair DNA with special attention paid to the XP proteins (XPA-G) as well as the DNA bypass polymerase POLH.
Figure A demonstrates the freckle-like pigmentation of XP in an 8-year-old girl who also has corneal scarring.
Figure B shows an infant with XP who has severe sunburns that were classified as second degree burns.