Splice site mutations in a xeroderma pigmentosum group A patient with delayed onset of neurological disease.

Abstract

XP12BE is a commonly studied XP-A cell line that exhibits slightly increased resistance to UV compared with the majority of XP-A cell lines. The elevated UV survival is common to a subset of XP-A cell lines and correlates with delayed onset of the neurological disease in patients. We identified the XPA mutations in XP12BE by single strand conformation polymorphism (SSCP) analyses and nucleotide sequencing. XP12BE is a compound heterozygote and both mutations affect mRNA splicing. One mutation is a G to C transversion within the splice donor site of intron 4 that is common to several cell lines from XP-A patients with delayed onset of neurological disease. The other mutation is a G to T transversion at the same position as a G to C transversion in the splice acceptor site of intron 3 that is common in Japanese XP-A patients. We also demonstrated the persistence of the XP12BE mutations in cell line 2-O-A2 which has been shown to express XPA protein. These results suggest that the intron 4 splice donor mutation likely produces some, at least partially functional, XPA protein that accounts for the increased UV survival of XP-A cell lines derived from patients with delayed onset of neurological disease.