The gene responsible for xeroderma pigmentosum (XP) group A has recently been cloned and designated XPA gene. Previous studies have shown that most Japanese. XPA patients have homozygous mutations for the splicing site of intron 3 of the XPA gene, which was recognized by restriction endonuclease (RE) AlwNI (AlwNI mutation). Other mutations found to date have been the nonsense mutation at codon 228 in exon 6, recognized by RE HphI (HphI mutation), and at codon 116 in exon 3, recognized by RE MseI (Msel mutation). Using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis, we examined the point mutations of the XPA gene in 16 XPA patients, their parents, and their four asymptomatic siblings, We found that eight patients were homozygous for the AlwNI mutation, two were compound heterozygotes for the AlwNI mutation and the HphI mutation, one was a compound heterozygote for the AlwNI mutation and the MseI mutation, three were compound heterozygotes for the AlwNI mutation and an unidentified mutation, and two were compound heterozygotes for the HphI mutation and an unidentified mutation, Investigation of their clinical features suggested that the four patients who were heterozygous for the HphI mutation and the AlwNI or an unidentified mutation had milder clinical manifestations such as later development of skin cancers and milder neurological deterioration, than those patients who were either homozygous for the AlwNI mutation or heterozygous for the AlwNI mutation and MseI mutation. PCR-RFLP analysis of the XPA gene in the four asymptomatic siblings of the XPA patients revealed that two were carriers of the mutated XPA allele, one was not a carrier, and one was not diagnosed because of the presence of an unidentified mutation, These data indicate that determination of the point mutation of the XPAC gene is important in predicting the clinical course in XPA patients, In addition, this method is useful for the detection of asymptomatic carriers in affected families, who have not been identified with conventional techniques.
