Distribution of mutations in the human xeroderma pigmentosum group A gene and their relationships to the functional regions of the DNA damage recognition protein

Abstract

A series of xeroderma pigmentosum group A cell lines from 19 patients and cell lines from 13 other family members were examined for XPA mutations to find previously unidentified mutations from American and European patients, to establish pedigrees in represented families, and to develop a database for XPA diagnosis. Most mutations were deletions and splice site mutations observed previously in other XPA patients, in exon III, intron III, or exon IV, that resulted in frameshifts within the DNA binding region—including an Afl III RFLP (G to C) in four unrelated families. One new mutation was a point mutation within intron III (A to G) creating a new splice acceptor site that may compete with the original splice acceptor site. Missplicing at this new site inserts 11 nucleotides in the mRNA creating a frameshift. A small amount of normal splicing to give wild‐type XPA protein is the likely molecular mechanism for the relatively mild clinical features of this patient. In another patient, a new 2 bp deletion in the RPA70 binding region was identified in the same region was identified in the same region as a 20 bp deletion previously characterized in an unrelated patient. Mutations in the DNA binding region of XPA were from patients with the more severe disease often associated with neurological complications, whereas mutations in the C‐terminal end of the protein, which interacts with the TFIIH transcription factor, were from patients with milder skin disease only. The rarity of naturally occurring missense mutations in the DNA binding region of XPA suggests that amino acid changes might be sufficiently tolerated that patients would have mild symptoms and escape detection. Hum Mutat 12:103–113, 1998.