Review Question - QID 107023

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.

Incorrect Answers:
Answer 2: Base excision repair removes bases that have been modified such as deaminated cytosines and is not affected in XP.
Answer 3: Mismatch repairs G/T or A/C pairing due to incorrect incorporation of nucleotides due to tautomerization of the nucleotide and is not involved in XP. Defects in the mismatch repair system are involved in hereditary nonpolyposis colorectal cancer (Lynch syndrome).
Answer 4: Homologous recombination (HR) repairs double stranded breaks by using the sister chromatid as the repair template and is not involved in XP. Defects in HR are involved in Bloom syndrome.
Answer 5: Non-homologous end joining (NHEJ) repairs double stranded breaks when a sister chromatid is not available as a template such a prior to S phases of the cell cycle. One of the many causes of severe combined immunodeficiency disease is a defect in NHEJ.