HOMOZYGOUS R788W POINT MUTATION IN THE XPF GENE OF A PATIENT WITH XERODERMA-PIGMENTOSUM AND LATE-ONSET NEUROLOGIC DISEASE

The second Caucasian xeroderma pigmentosum patient (XP42RO) belonging to complementation group F (XP-F) is described, Mild ocular photophobi a was present from childhood, and acute skin reactions occurred upon e xposure to sunlight. Basal and squamous cell carcinomas developed afte r his twenty-seventh year, In his late forties progressive neurologic symptoms emerged, which included intellectual decline, mild chorea and ataxia, and marked cerebral and cerebelar atrophy, Such neurologic ab normalities are very unusual in XP-F, Similar symptoms have been descr ibed in only one of 17 other XP-F individuals. His approximate to 5-fo ld reduced activity of nucleotide excision repair in cultured cells, c ombined with moderately affected cell survival and DNA replication aft er UV exposure, are typical of XP-F., The recent cloning of the XPF ge ne allowed a molecular genetic analysis of this unusual patient, XP42R O, representing the second case studied in this respect, turned out to be homozygous for a point mutation in the XPF gene, causing an R788-- >W substitution in the encoded protein, Surprisingly, this mutation ha d also been found in one allele of the other unrelated Caucasian XP-F case. The amount of mutated XPF protein is strongly reduced in cells f rom XP42RO, presumably due to a conformational change. Biochemical, ge netic, and clinical data all indicate the presence of considerable res idual repair activity, strongly suggesting that the R788W mutation is leaky.