Three genetic disorders, xeroderma pigmentosum (XP), Cockayne Syndrome (CS) and trichothiodystrophy (TTD) are all associated with defects in nucleotide excision repair (NER) of UV damage but their clinical features are quite different (Berneburg and Lehmann 2001) and they are all genetically complex (Lehmann, 2003). Seven genes are associated with XP (XPA - G), two with CS and three with TTD. In one gene, XPD, mutations can result in the highly cancer-prone skin disorder XP, in the non-cancer-prone multisystem disorder, TTD, or in patients with the clinical features of both XP and CS or XP and TTD (Broughton et al., 2001; Lehmann, 2001). A clue to how, in this one gene, mutations which cause similar DNA repair defects can result in completely different clinical entities came from the findings by Egly and co-workers several years ago that the XPD protein is a subunit of basal transcription factor TFIIH, which has two independent functions, in nucleotide excision repair and in basal transcription. The different clinical outcomes may result from mutations in the gene differentially affecting repair and transcription. We have identified the sites of mutations in different patients, and have demonstrated that the site of the mutation in the XPD gene does indeed determine the clinical outcome (Taylor et. al., 1997). Each mutation site is specific for one or other of the disease phenotypes. One particular mutation causing arginine-722 to be changed to histidine is found in several TTD patients. Colleagues in the Netherlands have generated a transgenic mouse containing this specific mutation, and this mouse had many of the features of TTD (De Boer et. al., 1998). Mutations resulting in the TTD phenotype are thought to be caused by alterations in transcription. We have obtained direct support for this idea by identifying a new clinical feature of TTD patients, namely beta-thalassaemia, caused by a specific defect in the synthesis of beta-globin mRNA (Viprakasit et al., 2001).

 
Diagnostic service

We run a diagnostic service for XP, CS and TTD, receiving patient samples from the UK and all over the world. We have developed simple cellular tests for these disorders that enable us to confirm or exclude the tentative clinical diagnoses. In 2010, we helped to establish and are part of a national multidisciplinary clinic for XP families.