ANALYSIS OF MUTATIONS IN THE XPD GENE IN ITALIAN PATIENTS WITH TRICHOTHIODYSTROPHY - SITE OF MUTATION CORRELATES WITH REPAIR DEFICIENCY, BUT GENE DOSAGE APPEARS TO DETERMINE CLINICAL SEVERITY

Xeroderma pigmentosum (XP) complementation group D is a heterogeneous group, containing patients with XP alone, rare cases with both XP and Cockayne syndrome, and patients with trichothiodystrophy (TTD). TTD is a rare autosomal recessive multisystem disorder associated, in many p atients, with a defect in nucleotide-excision repair; but in contrast to XP patients, TTD patients are not cancer prone. In most of the repa ir-deficient TTD patients, the defect has been assigned to the XPD gen e. The XPD gene product is a subunit of transcription factor TFILH, wh ich is involved in both DNA repair and transcription. We have determin ed the mutations and the pattern of inheritance of the XPD alleles in the 11 cases identified in Italy so far, in which the hair abnormaliti es diagnostic for TTD are associated with different disease severity b ut similar cellular photosensitivity. We have identified eight causati ve mutations, of which four have not been described before, either in T-TD or XP cases, supporting the hypothesis that the mutations respons ible for TTD are different from those found in other pathological phen otypes. Arg112his was the most common alteration in the Italian patien ts, of whom five were homozygotes and two were heterozygotes, for this mutation. The presence of a specifically mutated XPD allele, irrespec tive of its homozygous, hemizygous, or heterozygous condition, was alw ays associated with the same degree of cellular UV hypersensitivity. S urprisingly, however, the severity of the clinical symptoms did not co rrelate with the magnitude of the DNA-repair defect. The most severe c linical features were found in patients who appear to be functionally hemizygous for the mutated allele.