Mutations in the XPD gene leading to xeroderma pigmentosum symptoms

Abstract

XP is a sun-sensitive and cancer-prone genetic disorder, consisting of eight (group A-G) genetically distinct complementation groups. Some XP group D patients exhibit clinical symptoms of other genetic disorders, 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 transcription factor TFIIH as well. Therefore, different mutations in the XPD gene may result in a variety of clinical manifestations. Here we report 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 truncation of the protein. The other was a nucleotide substitution leading 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 were obligate carriers of the XP-D trait. The expression study showed that the XPD cDNA containing the deletion or the S541R missense mutation failed to restore the UV sensitivity of XP6BE, group DaXP 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 slightly more resistant than the parental XP6BE cells. These findings are consistent with the mild symptoms of the XP61OS patient.

Functional TFIIH Is Required for UV-Induced Translocation of CSA to the Nuclear Matrix

“…The cell lines used in this study were simian virus 40-immortalized human fibroblasts: WI38VA13 (normal), CS3BESV (CS-A), CS1ANSV (CS-B), XP2OSSV (XP-A), XP4PASV (XP-C), XP6BESV (XP-D), XPCS2SV (XP-D/CS), XPCS2BASV (XP-B/CS), TTD1ROSV (XP-D/TTD), and TTD1BRSV (TTD-A). XP6BESV and XPCS2SV cells stably expressing XPD (XPD/XP6BESV and XPD/XPCS2SV) were isolated as described previously (17). The transfectants showed almost the same level of UV resistance as WI38VA13 cells (data not shown).…”

The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases

“…The work described in the previous section has shown that for the essential role of TFIIH in transcription, the main function of the XPD protein is to maintain the stability of the TFIIH complex. As a consequence, the XPD gene is rather tolerant of mutations, and indeed many different viable mutations have been detected in patients in the XP-D group (Broughton et al 1994;Takayama et al 1995Takayama et al , 1996Kobayashi et al 1997;Taylor et al 1997;Botta et al 1998). For its DNA repair function, however, XPD needs to be not only present but also enzymatically active.…”

Phenotype-specific adverse effects of XPD mutations on human prenatal development implicate impairment of TFIIH-mediated functions in placenta

“…8 Neonatal history was not reported for the one patient with XP/CS identified through the literature. 38 Mapping of preeclampsia-associated domains on XPD All TTD (n¼8) 8,20,21 and XP (n¼3) 30,36,37 cases with known XPD mutations and explicit information on presence or absence of preeclampsia were included in the analysis to map the preeclampsiaassociated alleles onto XPD. Of the eight TTD (including one COFS/TTD) pregnancies, four were associated with preeclampsia and all eight were associated with at least one prenatal complication.…”

“…All case reports in English and French were included; reports in other languages were included if the abstract was in either English or French. A total of 43 TTD, 9-22 37 XP, [23][24][25][26][27][28][29][30][31][32][33][34][35] six XP/TTD, 3,8 four XP/CS, [36][37][38] and 1 COFS/TTD 8 patient with defects in the XPD gene were identified and included in our study population.…”