An 8-year-old girl is brought to a dermatologist because of multiple hyperpigmented macules on her face. She has a history of sun sensitivity, and develops severe sunburn after only a short time in the sun, with the sunburn often lasting for several weeks. On examination, her eyes appear irritated. She also has many freckles and her skin feels thick and dry. Biopsy of the lesion shows both basal and squamous cell carcinomas.

What is the most likely diagnosis?

Xeroderma pigmentosum (XP), a genetic disorder of DNA repair mechanisms.

What is the inheritance pattern of this condition?

XP is inherited in an autosomal recessive manner. A number of different genes can give rise to the disorder. The disease prevalence in the U.S. is 1 in 250,000.

What is the role of the genes that are mutated in this condition?

In XP there are mutations in the genes that encode enzymes involved in nucleotide excision repair (NER). On exposure to ultraviolet (UV) light, covalent adducts such as thymidine dimers can form between DNA bases on the same strand. NER enzymes are responsible for repairing the affected region. NER involves excision of the DNA segment with the lesion by endonucleases, leaving a single-strand DNA template that is later filled in by DNA polymerase and sealed with DNA ligase. Individuals with this disorder must avoid sunlight, as they are at high risk for basal and squamous cell carcinoma following exposure to UV light.

What other repair mechanisms are used by the cell?

Base excision repair involves the removal of damaged bases. Ultraviolet light and free radicals are frequent causes of damage to the DNA bases. The glycosidic bond between the base and the ribose group is cleaved by a glycosylase, followed by nicking of the DNA to the 5¢ side of the removed base. DNA synthesis from this nick restores the removed nucleotide. Mismatch repair and base excision repair are two other DNA repair mechanisms. Mismatch occurs when the incorrect nucleotide is incorporated during DNA replication. The newly synthesized strand can be distinguished from the template strand by the repair enzymes. The region on the newly synthesized strand involving the mismatch is removed, and the template strand is used to synthesize a complementary DNA sequence. Mutations in mismatch repair genes are responsible for hereditary nonpolyposis colorectal cancer.

What are the major transcription products of the three eukaryotic RNA polymerases?

In eukaryotes RNA polymerase I transcribes rRNA, RNA polymerase II transcribes mRNA, and RNA polymerase III transcribes tRNA. In prokaryotes there is only one RNA polymerase, and it can synthesize all three classes of RNA.

By Christina L. Shenvi, PhD, class of 2009, Yale University School of Medicine; in association with Le TT, Takiar V, eds: First Aid Cases for the USMLE Step 1. New York: McGraw-Hill, 2009.