Analysis of mutations in the XPD gene in Italian patients with trichothiodystrophy: site of mutation correlates with repair deficiency, but gene dosage appears to determine clinical severity.

Xeroderma pigmentosum (XP) complementation group D is a heterogeneous group, containing patients with XP alone, rare cases with both XP and Cockayne syndrome, and patients with trichothiodystrophy (TTD). TTD is a rare autosomal recessive multisystem disorder associated, in many patients, with a defect in nucleotide-excision repair; but in contrast to XP patients, TTD patients are not cancer prone. In most of the repair-deficient TTD patients, the defect has been assigned to the XPD gene. The XPD gene product is a subunit of transcription factor TFIIH, which is involved in both DNA repair and transcription. We have determined the mutations and the pattern of inheritance of the XPD alleles in the 11 cases identified in Italy so far, in which the hair abnormalities diagnostic for TTD are associated with different disease severity but similar cellular photosensitivity. We have identified eight causative mutations, of which four have not been described before, either in TTD or XP cases, supporting the hypothesis that the mutations responsible for TTD are different from those found in other pathological phenotypes. Arg112his was the most common alteration in the Italian patients, of whom five were homozygotes and two were heterozygotes, for this mutation. The presence of a specifically mutated XPD allele, irrespective of its homozygous, hemizygous, or heterozygous condition, was always associated with the same degree of cellular UV hypersensitivity. Surprisingly, however, the severity of the clinical symptoms did not correlate with the magnitude of the DNA-repair defect. The most severe clinical features were found in patients who appear to be functionally hemizygous for the mutated allele.

[1]  L. Thompson,et al.  Molecular cloning and biological characterization of a human gene, ERCC2, that corrects the nucleotide excision repair defect in CHO UV5 cells , 1988, Molecular and cellular biology.

[2]  E. Friedberg,et al.  Correction of xeroderma pigmentosum complementation group D mutant cell phenotypes by chromosome and gene transfer: involvement of the human ERCC2 DNA repair gene. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[3]  A. Lehmann,et al.  Xeroderma pigmentosum and trichothiodystrophy are associated with different mutations in the XPD (ERCC2) repair/transcription gene. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[4]  A. Carrano,et al.  Cloning and molecular characterization of the Chinese hamster ERCC2 nucleotide excision repair gene. , 1994, Genomics.

[5]  J. Hoeijmakers,et al.  Molecular and cellular analysis of the DNA repair defect in a patient in xeroderma pigmentosum complementation group D who has the clinical features of xeroderma pigmentosum and Cockayne syndrome. , 1995, American journal of human genetics.

[6]  B. Rost,et al.  Combining evolutionary information and neural networks to predict protein secondary structure , 1994, Proteins.

[7]  L. Thompson,et al.  ERCC2: cDNA cloning and molecular characterization of a human nucleotide excision repair gene with high homology to yeast RAD3. , 1990, The EMBO journal.

[8]  E. Friedberg,et al.  Structural and mutational analysis of the xeroderma pigmentosum group D (XPD) gene. , 1994, Human molecular genetics.

[9]  S. Giliani,et al.  Xeroderma pigmentosum complementation group H falls into complementation group D. , 1991, Mutation research.

[10]  D. Easton,et al.  ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. , 1998, American journal of human genetics.

[11]  S. Giliani,et al.  Genetic heterogeneity of the excision repair defect associated with trichothiodystrophy. , 1993, Carcinogenesis.

[12]  H. Steingrimsdottir,et al.  Trichothiodystrophy, a human DNA repair disorder with heterogeneity in the cellular response to ultraviolet light. , 1988, Cancer research.

[13]  S. Giliani,et al.  Molecular analysis of the XP-D gene in Italian families with patients affected by trichothiodystrophy and xeroderma pigmentosum group D. , 1994, Mutation research.

[14]  D. Reinberg,et al.  Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II , 1994, Nature.

[15]  P. Itin,et al.  Trichothiodystrophy: review of sulfur-deficient brittle hair syndromes and association with the ectodermal dysplasias. , 1990, Journal of the American Academy of Dermatology.

[16]  J. Hoeijmakers,et al.  Engagement with transcription , 1993, Nature.

[17]  R. Nairn,et al.  Characterization of the Xiphophorus fish (Teleostei: Poeciliidae) ERCC2/XPD locus. , 1995, Genomics.

[18]  Burkhard Rost,et al.  PHD - an automatic mail server for protein secondary structure prediction , 1994, Comput. Appl. Biosci..

[19]  P. Sung,et al.  Human xeroderma pigmentosum group D gene encodes a DMA helicase , 1993, Nature.

[20]  J. Hoeijmakers,et al.  The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor. , 1994, The EMBO journal.

[21]  S. Giliani,et al.  DNA repair investigations in nine Italian patients affected by trichothiodystrophy. , 1992, Mutation research.

[22]  Y. Nakatsu,et al.  Mutations in the XPD gene leading to xeroderma pigmentosum symptoms , 1997, Human mutation.

[23]  P. Hanawalt,et al.  Competent transcription initiation by RNA polymerase II in cell-free extracts from xeroderma pigmentosum groups B and D in an optimized RNA transcription assay. , 1997, Biochimica et biophysica acta.

[24]  L. Thompson,et al.  Defects in the DNA repair and transcription gene ERCC2 in the cancer-prone disorder xeroderma pigmentosum group D. , 1995, Cancer research.

[25]  W. Vermeulen,et al.  Three unusual repair deficiencies associated with transcription factor BTF2(TFIIH): evidence for the existence of a transcription syndrome. , 1994, Cold Spring Harbor symposia on quantitative biology.

[26]  J. Hoeijmakers,et al.  TFIIH: a key component in multiple DNA transactions. , 1996, Current opinion in genetics & development.

[27]  J. Tolmie,et al.  Syndromes associate with trichotodystrophy , 1994 .

[28]  J. Hoeijmakers,et al.  Disruption of the mouse xeroderma pigmentosum group D DNA repair/basal transcription gene results in preimplantation lethality. , 1998, Cancer research.

[29]  H. Steingrimsdottir,et al.  Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with trichothiodystrophy , 1994, Nature Genetics.

[30]  S. Giliani,et al.  A new nucleotide-excision-repair gene associated with the disorder trichothiodystrophy. , 1993, American journal of human genetics.

[31]  G. Zei,et al.  Search for consanguinity within and among families of patients with trichothiodystrophy associated with xeroderma pigmentosum. , 1990, Journal of medical genetics.

[32]  D. Danks,et al.  DNA repair characteristics and mutations in the ERCC2 DNA repair and transcription gene in a trichothiodystrophy patient , 1997, Human mutation.

[33]  F. Z. Watts,et al.  Cloning and characterisation of the S. pombe rad15 gene, a homologue to the S. cerevisiae RAD3 and human ERCC2 genes. , 1992, Nucleic acids research.

[34]  R. Scott,et al.  Clinical heterogeneity within xeroderma pigmentosum associated with mutations in the DNA repair and transcription gene ERCC3. , 1994, American journal of human genetics.

[35]  H. Steingrimsdottir,et al.  Five polymorphisms in the coding sequence of the xeroderma pigmentosum group D gene. , 1996, Mutation research.

[36]  G. Ehrlich,et al.  The Metabolic Basis Of Inherited Disease. , 1973 .

[37]  L. Thompson,et al.  Defects in the DNA repair and transcription gene ERCC2(XPD) in trichothiodystrophy. , 1996, American journal of human genetics.

[38]  B. Rost,et al.  Prediction of protein secondary structure at better than 70% accuracy. , 1993, Journal of molecular biology.