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Human Molecular Genetics, 2001, Vol. 10, No. 22 2539-2547
© 2001 Oxford University Press

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

Bernard C. Broughton, Mark Berneburg1, Heather Fawcett, Elaine M. Taylor, Colin F. Arlett, Tiziana Nardo2, Miria Stefanini2, Emory Menefee3, Vera H. Price3, Sophie Queille4, Alain Sarasin4, Elisabeth Bohnert5, Jean Krutmann1, Rosemarie Davidson6, Kenneth H. Kraemer7 and Alan R. Lehmann+

Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RR, UK, 1Clinical and Experimental Photodermatology, Heinrich-Heine-Universität, Moorenstrasse 5, 40225 Düsseldorf, Germany, 2Istituto di Genetica Biochimica ed Evolutionistica CNR, Via Abbiategrasso 207, Pavia, Italy, 3Trichos Research, 5313 Rosalind Avenue, Richmond, CA 94805, USA, 4Laboratory of Molecular Genetics, UPR 2169-CNRS, BP 8, 94801, Villejuif, France, 5Facultät fur Klinische Medizin Mannheim der Universität Heidelberg, 68135 Mannheim, Germany, 6Department of Medical Genetics, Yorkhill NHS Trust, Glasgow G3 8SJ, UK and 7Basic Research Laboratory, National Cancer Institute, Bethesda, MD 20892, USA

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 hairshafts 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.

+ To whom correspondence should be addressed. Tel: +44 1273 678120; Fax: +44 1273 678121; Email: a.r.lehmann@sussex.ac.ukThe authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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