Our results suggested a link between TTD- but not XP-associated XPD mutations, placental maldevelopment and risk of pregnancy complications, possibly due to impairment of TFIIH-mediated functions in placenta.
Thus, mutations in TFIIH components may, on top of a repair defect, also cause transcriptional insufficiency, which may explain part of the non-XP clinical features of TTD.
XPB or XPD missense mutations lead to Xeroderma pigmentosum, Cockayne's syndrome, Trichothiodystrophy, or COFS syndrome, suggesting that DNA repair and transcription defects are responsible for clinical heterogeneity.
For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG).
Transfection and microinjection experiments demonstrated that mutations in ERCC3 are responsible for XP complementation group B, a very rare form of XP that is simultaneously associated with Cockayne's syndrome (CS).
These cell lines result from a stable transfection of the XPB-TTD allele into XP complementation group B fibroblasts, from an XP patient who also have clinical abnormalities corresponding to Cockayne's syndrome (CS).
The subtle transcriptional differences found between various TFIIH variants thus participate in the phenotypic variability observed among XP, XP/CS, and TTD individuals.
Amino acid sequence analysis of the tryptic digest generated from the 89-kilodalton subunit of BTF2 indicated that this polypeptide corresponded to the ERCC-3 gene product, a presumed helicase implicated in the human DNA excision repair disorders xeroderma pigmentosum and Cockayne's syndrome.
The clinical features of CS can also accompany the excision repair-defective hereditary disorder xeroderma pigmentosum (XP) from genetic complementation groups B, D or G. The XPB and XPD proteins are subunits of RNA polymerase II (RNAP II) transcription factor IIH (TFIIH).