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Human Molecular Genetics, 2001, Vol. 10, No. 24 2797-2802
© 2001 Oxford University Press

Mutations in the general transcription factor TFIIH result in ß-thalassaemia in individuals with trichothiodystrophy

Vip Viprakasit, Richard J. Gibbons1, Bernard C. Broughton2, John L. Tolmie3, Donald Brown4, Peter Lunt5, Robin M. Winter6, Stefano Marinoni7, Miria Stefanini8, Louise Brueton9, Alan R. Lehmann2,+ and Douglas R. Higgs

MRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK, 1Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK, 2Genome Damage and Stability Centre, School of Biological Sciences, University of Sussex, Brighton BN1 9RR, UK, 3Duncan Guthrie Institute of Medical Genetics, York Hill Hospital, Glasgow G3 8SJ, UK, 4University of Edinburgh, Edinburgh, UK, 5Institute of Child Health, Bristol Royal Hospital for Sick Children, Bristol B32 8BJ, UK, 6Clinical Genetics Unit, Great Ormond Street Hospital and Institute of Child Health, London WC1N 1EH, UK, 7Istituto per l’Infanzia, Trieste, Italy, 8Istituto di Genetica, Biochimica ed Evolutionistica CNR, Via Abbiategrasso 207, Pavia, Italy and 9Clinical Genetics Unit, Birmingham Women’s Hospital, Birmingham B15 2TG, UK

The transcription factor TFIIH is involved in both basal transcription and DNA repair. Mutations in the XPD helicase component of TFIIH can result in the diverse clinical features associated with xeroderma pigmentosum (XP) and trichothiodystrophy (TTD). It is generally believed that the multi-system abnormalities associated with TTD are the result of a subtle deficiency in basal transcription. However, to date, there has been no clear demonstration of a defect in expression of any specific gene in individuals with these syndromes. Here we show that the specific mutations in XPD that cause TTD result in reduced expression of the ß-globin genes in these individuals. Eleven TTD patients with characterized mutations in the XPD gene have the haematological features of ß-thalassaemia trait, and reduced levels of ß-globin synthesis and ß-globin mRNA. All these parameters were normal in three patients with XP. These findings provide the first evidence for reduced expression of a specific gene in TTD. They support the hypothesis that many of the clinical features of TTD result from inadequate expression of a diverse set of highly expressed genes.

+ To whom correspondence should be addressed. Tel: +44 1273 678120; Fax: +44 1273 678121; Email: a.r.lehmann@sussex.ac.uk


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