Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations in the XPD gene

Abstract

The xeroderma pigmentosum group D (XPD) protein is a subunit of transcription factor TFIIH with DNA helicase activity. TFIIH has two functions, in basal transcription and nucleotide excision repair. Mutations in XPD that affect DNA repair but not transcription result in the skin cancer-prone disorder, xeroderma pigmentosum (XP). If transcription is also affected, the result is the multi-system disorder trichothiodystrophy (TTD), in which there is no skin cancer predisposition, or in rare cases, XP combined with Cockayne syndrome. Up till now there have been no reports of combined clinical features of XP and TTD. We have now identified two patients with some features of both these disorders. One of these, XP189MA, a 3-year-old girl with sun sensitivity, mental and physical developmental delay, has XPD mutations not previously reported, and barely detectable levels of nucleotide excision repair. The other, XP38BR, a 28-year-old woman with sun sensitivity, pigmentation changes and skin cancers typical of XP, has a mutation that has been identified previously, but only in TTD patients with no features of XP. The level of repair of UV damage in XP38BR is substantially higher than that in other patients with the same mutation. With both patients, polarized light microscopy revealed a 'tiger-tail' appearance of the hair, and amino acid analysis of the hair shafts show levels of sulfur-containing proteins intermediate between those of normal and TTD individuals. Our findings highlight the complexities of genotype-phenotype relationships in the XPD gene.

DNA charge transport as a first step in coordinating the detection of lesions by repair proteins

“…XPD, a superfamily 2 DNA helicase with 5′-3′ polarity, is a component of TFIIH that is essential for repair of bulky lesions generated by exogenous sources such as UV light and chemical carcinogens (28,46,47). XPD contains a conserved [4Fe-4S] cluster suggested to be conformationally controlled by ATP binding and hydrolysis (25).…”

A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A

“…Photosensitive features of xeroderma pigmentosum are caused by defective NER, whereas features of Cockayne syndrome and TTD are attributed to defective TCR and transcription function. Most individuals with these syndromes associated with TFIIH carry mutations of XPD or, in a few cases, of XPB, the two TFIIH helicase subunits [9][10][11][12] . A third, unidentified gene that causes photosensitive TTD 13,14 , called GTF2H5, also shows association with TFIIH 1 .…”

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

“…Five of six patients with XPD-associated XP/TTD were not noted to have any gestational complications; 3,8 one XPDassociated XP/TTD case was reported as having low birth weight, SGAo3rd percentile, and NICU admission. 3 Pregnancy with the one patient with COFS/TTD reported in the literature was complicated with preeclampsia, HELLP syndrome, pre-term delivery, low birth weight, SGAo3rd percentile, and NICU admission. 8 Neonatal history was not reported for the one patient with XP/CS identified through the literature.…”

“…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.…”

“…1 Besides TTD, mutations in XPD (ERCC2) can lead to several other DNA repair disorders including xeroderma pigmentosum (XP), Cockayne syndrome (CS), cerebroocular facial syndrome (COFS) or a combination of XP/TTD, XP/CS, or COFS/TTD. [1][2][3][4] XPD, XPB, and TTD-A code for components of the seven-subunit core complex of transcription factor (TF) IIH. TFIIH also contains a three-subunit Cdk-activating kinase (CAK) complex composed of cdk7, MAT1, and cyclin H. 5 TFIIH has a role in NER and in both basal and activated transcription; 6 as a component of RNA polymerase-II (Pol-II) transcription machinery, TFIIH has an important role in RNA Pol-II elongation.…”