DISTRIBUTION OF MUTATIONS IN THE HUMAN XERODERMA-PIGMENTOSUM GROUP-A GENE AND THEIR RELATIONSHIPS TO THE FUNCTIONAL REGIONS OF THE DNA-DAMAGE RECOGNITION PROTEIN

A series of xeroderma pigmentosum group A cell lines from 19 patients and cell lines from 13 other family members were examined for XPA muta tions to find previously unidentified mutations from American and Euro pean patients, to establish pedigrees in represented families, and to develop a database for XPA diagnosis. Most mutations were deletions an d 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 unre lated families. One new mutation was a point mutation within intron II I (A to G) creating a new splice acceptor site that may compete with t he original splice acceptor site. Missplicing at this new site inserts 11 nucleotides in the mRNA creating a frameshift, A small amount of n ormal splicing to give wild-type XPA protein is the likely molecular m echanism 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 as a 20 bp deletion previously character ized in an unrelated patient. Mutations in the DNA binding region of X PA were from patients with the more severe disease often associated wi th 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 natura lly occurring missense mutations in the DNA binding region of XPA sugg ests that amino acid changes might be sufficiently tolerated that pati ents would have mild symptoms and escape detection, Hum Mutat 12:103-1 13, 1998. (C) 1998 Wiley-Liss, Inc.