DEFECTS IN THE DNA-REPAIR AND TRANSCRIPTION GENE ERCC2(XPD) IN TRICHOTHIODYSTROPHY

Trichothiodystrophy (TTD) is a rare autosomal recessive disorder chara cterized by brittle hair with reduced sulfur content, ichthyosis, pecu liar face, and mental and growth retardation. Clinical photosensitivit y is present in similar to 50% of TTD patients but is not associated w ith an elevated frequency of cancers. Previous complementation studies show that the photosensitivity in nearly all of the studied patients is due to a defect in the same genetic locus that underlies the cancer -prone genetic disorder xeroderma pigmentosum group D (XP-D). Nucleoti de-sequence analysis of the ERCC2 cDNA from three TTD cell strains (TT D1VI, TTD3VI, and TTD1RO) revealed mutations within the region from am ino acid 713-730 and within previously identified helicase functional domains. The various clinical presentations and DNA repair characteris tics of the cell strains can be correlated with the particular mutatio ns found in the ERCC2 locus. Mutations of Arg658 to either His or Cys correlate with TTD cell strains with intermediate UV-sensitivity, muta tion of Arg722 to Trp correlates with highly UV-sensitive TTD cell str ains, and mutation of Arg683 to Trp correlates with XP-D. Alleles with mutation of Arg616 to Pro or with the combined mutation of Leu461 to Val and deletion of 716-730 are found in both XP-D and TTD cell strain s.