MUTATIONS IN THE XPD GENE LEADING TO XERODERMA-PIGMENTOSUM SYMPTOMS

XP is a sun-sensitive and cancer prone genetic disorder, consisting of eight (group A-G) genetically distinct complementation groups, Some X P group D patients exhibit clinical symptoms of other genetic disorder s, CS, and TTD, The XP group D gene (XPD gene) product is required for nucleotide excision repair and is one of the components of basal tran scription factor TFIIH as well, Therefore, different mutations in the XPD gene may result in a variety of clinical manifestations, Here we r eport on two causative mutations of the XPD gene in XP61OS, a Japanese XP group D patient who has only mild skin symptoms of XP without CS, TTD, or other neurological complications. One of the mutations was the 4-bp deletion at nucleotides 668-671, resulting in frameshift and tru ncation of the protein, The other was a nucleotide substitution leadin g to Ser-541 to Arg (S541R) in helicase domain IV of the XPD protein. The patient's father was heterozygous for the 4-bp deletion, while the mother was heterozygous for the S541R mutation. Thus, the parents wer e obligate carriers of the XP-D trait, The expression study showed tha t the XPD cDNA containing the deletion or the S541R missense mutation failed to restore the UV sensitivity of XP6BE, group D XP cells, while the wild-type XPD cDNA. restored it to the normal level, However, the transfectant expressing the XPD cDNA with the missense mutation was s lightly more resistant than the parental XP6BE cells. These findings a pe consistent with the mild symptoms of the XP610S patient. (C) 1991 W iley-Liss, Inc.