A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy

Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and nails, mental retardation, impaired sexual development, and ichthyosis. Photosensitivity has been reported in approximately 50% of the cases, but no skin cancer is associated with TTD...

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Veröffentlicht in:American journal of human genetics 1997-02, Vol.60 (2), p.320-329
Hauptverfasser: WEEDA, G, EVENO, E, DONKER, I, VERMEULEN, W, CHEVALLIER-LAGENTE, O, TAÏEB, A, STARY, A, HOEIJMAKERS, J. H. J, MEZZINA, M, SARASIN, A
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creator WEEDA, G
EVENO, E
DONKER, I
VERMEULEN, W
CHEVALLIER-LAGENTE, O
TAÏEB, A
STARY, A
HOEIJMAKERS, J. H. J
MEZZINA, M
SARASIN, A
description Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and nails, mental retardation, impaired sexual development, and ichthyosis. Photosensitivity has been reported in approximately 50% of the cases, but no skin cancer is associated with TTD. Virtually all photosensitive TTD patients have a deficiency in the nucleotide excision repair (NER) of UV-induced DNA damage that is indistinguishable from that of xeroderma pigmentosum (XP) complementation group D (XP-D) patients. DNA repair defects in XP-D are associated with two additional, quite different diseases; XP, a sun-sensitive and cancer-prone repair disorder, and Cockayne syndrome (CS), a photosensitive condition characterized by physical and mental retardation and wizened facial appearance. One photosensitive TTD case constitutes a new repair-deficient complementation group, TTD-A. Remarkably, both TTD-A and XP-D defects are associated with subunits of TFIIH, a basal transcription factor with a second function in DNA repair. Thus, mutations in TFIIH components may, on top of a repair defect, also cause transcriptional insufficiency, which may explain part of the non-XP clinical features of TTD. Besides XPD and TTDA, the XPB gene product is also part of TFIIH. To date, three patients with the remarkable conjunction of XP and CS but not TTD have been assigned to XP complementation group B (XP-B). Here we present the characterization of the NER defect in two mild TTD patients (TTD6VI and TTD4VI) and confirm the assignment to X-PB. The causative mutation was found to be a single base substitution resulting in a missense mutation (T119P) in a region of the XPB protein completely conserved in yeast, Drosophila, mouse, and man. These findings define a third TTD complementation group, extend the clinical heterogeneity associated with XP-B, stress the exclusive relationship between TTD and mutations in subunits of repair/transcription factor TFIIH, and strongly support the concept of "transcription syndromes."
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DNA repair defects in XP-D are associated with two additional, quite different diseases; XP, a sun-sensitive and cancer-prone repair disorder, and Cockayne syndrome (CS), a photosensitive condition characterized by physical and mental retardation and wizened facial appearance. One photosensitive TTD case constitutes a new repair-deficient complementation group, TTD-A. Remarkably, both TTD-A and XP-D defects are associated with subunits of TFIIH, a basal transcription factor with a second function in DNA repair. Thus, mutations in TFIIH components may, on top of a repair defect, also cause transcriptional insufficiency, which may explain part of the non-XP clinical features of TTD. Besides XPD and TTDA, the XPB gene product is also part of TFIIH. To date, three patients with the remarkable conjunction of XP and CS but not TTD have been assigned to XP complementation group B (XP-B). Here we present the characterization of the NER defect in two mild TTD patients (TTD6VI and TTD4VI) and confirm the assignment to X-PB. The causative mutation was found to be a single base substitution resulting in a missense mutation (T119P) in a region of the XPB protein completely conserved in yeast, Drosophila, mouse, and man. 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H. J</creatorcontrib><creatorcontrib>MEZZINA, M</creatorcontrib><creatorcontrib>SARASIN, A</creatorcontrib><title>A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy</title><title>American journal of human genetics</title><addtitle>Am J Hum Genet</addtitle><description>Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and nails, mental retardation, impaired sexual development, and ichthyosis. Photosensitivity has been reported in approximately 50% of the cases, but no skin cancer is associated with TTD. Virtually all photosensitive TTD patients have a deficiency in the nucleotide excision repair (NER) of UV-induced DNA damage that is indistinguishable from that of xeroderma pigmentosum (XP) complementation group D (XP-D) patients. DNA repair defects in XP-D are associated with two additional, quite different diseases; XP, a sun-sensitive and cancer-prone repair disorder, and Cockayne syndrome (CS), a photosensitive condition characterized by physical and mental retardation and wizened facial appearance. One photosensitive TTD case constitutes a new repair-deficient complementation group, TTD-A. Remarkably, both TTD-A and XP-D defects are associated with subunits of TFIIH, a basal transcription factor with a second function in DNA repair. Thus, mutations in TFIIH components may, on top of a repair defect, also cause transcriptional insufficiency, which may explain part of the non-XP clinical features of TTD. Besides XPD and TTDA, the XPB gene product is also part of TFIIH. To date, three patients with the remarkable conjunction of XP and CS but not TTD have been assigned to XP complementation group B (XP-B). Here we present the characterization of the NER defect in two mild TTD patients (TTD6VI and TTD4VI) and confirm the assignment to X-PB. The causative mutation was found to be a single base substitution resulting in a missense mutation (T119P) in a region of the XPB protein completely conserved in yeast, Drosophila, mouse, and man. 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Haemangioma of the skin, of mucosae and of soft tissue</subject><subject>Humans</subject><subject>Ichthyosis - genetics</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mutation</subject><subject>Photosensitivity Disorders - genetics</subject><subject>Transcription Factor TFIIH</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors, TFII</subject><subject>Transcription, Genetic</subject><subject>Ultraviolet Rays</subject><subject>Xeroderma Pigmentosum - genetics</subject><issn>0002-9297</issn><issn>1537-6605</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkFFLwzAUhYsoc05_gpAHEQSLuU3Tpi9CrdMJQ0UUfLKkabZG2qY26WT_3urKUJ8u3PPdcw9nxxkDJaEbBJjuOmOMsedGXhTuOwfGvGMMwDAZOaMIg-djOnbeYlR1llula6RqZAuJXh-vLqZPSULQ9X2MWtlw1SLb8tqIVjU_5FLW8hxxY7RQ3MocfSpb9IwShbaF0vna2FY3xfrQ2Vvw0sijYU6cl5vpczJz5w-3d0k8dwviBdZlfg6CcBoIInzgYsFyAiSKhJA8D3hG_QgzFsiM5hkJABPm5VhSCj6NQp9TMnEuN75Nl1UyF7LuA5dp06qKt-tUc5X-VWpVpEu9SiEEj0SsNzjbGBT_zmbxPP3eYQ-A-iFbQc-eDs9a_dFJY9NKGSHLktdSdyYNGcNAIezB49-ptr5D-71-MujcCF4u-o6FMlvMozRkEJAvgdCOdw</recordid><startdate>19970201</startdate><enddate>19970201</enddate><creator>WEEDA, G</creator><creator>EVENO, E</creator><creator>DONKER, I</creator><creator>VERMEULEN, W</creator><creator>CHEVALLIER-LAGENTE, O</creator><creator>TAÏEB, A</creator><creator>STARY, A</creator><creator>HOEIJMAKERS, J. 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Haemangioma of the skin, of mucosae and of soft tissue</topic><topic>Humans</topic><topic>Ichthyosis - genetics</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mutation</topic><topic>Photosensitivity Disorders - genetics</topic><topic>Transcription Factor TFIIH</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors, TFII</topic><topic>Transcription, Genetic</topic><topic>Ultraviolet Rays</topic><topic>Xeroderma Pigmentosum - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>WEEDA, G</creatorcontrib><creatorcontrib>EVENO, E</creatorcontrib><creatorcontrib>DONKER, I</creatorcontrib><creatorcontrib>VERMEULEN, W</creatorcontrib><creatorcontrib>CHEVALLIER-LAGENTE, O</creatorcontrib><creatorcontrib>TAÏEB, A</creatorcontrib><creatorcontrib>STARY, A</creatorcontrib><creatorcontrib>HOEIJMAKERS, J. H. 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J</au><au>MEZZINA, M</au><au>SARASIN, A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy</atitle><jtitle>American journal of human genetics</jtitle><addtitle>Am J Hum Genet</addtitle><date>1997-02-01</date><risdate>1997</risdate><volume>60</volume><issue>2</issue><spage>320</spage><epage>329</epage><pages>320-329</pages><issn>0002-9297</issn><eissn>1537-6605</eissn><coden>AJHGAG</coden><abstract>Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and nails, mental retardation, impaired sexual development, and ichthyosis. Photosensitivity has been reported in approximately 50% of the cases, but no skin cancer is associated with TTD. Virtually all photosensitive TTD patients have a deficiency in the nucleotide excision repair (NER) of UV-induced DNA damage that is indistinguishable from that of xeroderma pigmentosum (XP) complementation group D (XP-D) patients. DNA repair defects in XP-D are associated with two additional, quite different diseases; XP, a sun-sensitive and cancer-prone repair disorder, and Cockayne syndrome (CS), a photosensitive condition characterized by physical and mental retardation and wizened facial appearance. One photosensitive TTD case constitutes a new repair-deficient complementation group, TTD-A. Remarkably, both TTD-A and XP-D defects are associated with subunits of TFIIH, a basal transcription factor with a second function in DNA repair. Thus, mutations in TFIIH components may, on top of a repair defect, also cause transcriptional insufficiency, which may explain part of the non-XP clinical features of TTD. Besides XPD and TTDA, the XPB gene product is also part of TFIIH. To date, three patients with the remarkable conjunction of XP and CS but not TTD have been assigned to XP complementation group B (XP-B). Here we present the characterization of the NER defect in two mild TTD patients (TTD6VI and TTD4VI) and confirm the assignment to X-PB. The causative mutation was found to be a single base substitution resulting in a missense mutation (T119P) in a region of the XPB protein completely conserved in yeast, Drosophila, mouse, and man. These findings define a third TTD complementation group, extend the clinical heterogeneity associated with XP-B, stress the exclusive relationship between TTD and mutations in subunits of repair/transcription factor TFIIH, and strongly support the concept of "transcription syndromes."</abstract><cop>Chicago, IL</cop><pub>University of Chicago Press</pub><pmid>9012405</pmid><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-2445-6016</orcidid><orcidid>https://orcid.org/0000-0002-7282-280X</orcidid></addata></record>
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source MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central
subjects Adolescent
Biological and medical sciences
Cells, Cultured
Child
Dermatology
DNA Helicases
DNA Repair
DNA, Complementary - genetics
DNA-Binding Proteins - genetics
Female
Genetic Complementation Test
Hair Diseases - genetics
Hereditary diseases of the skin. Congenital diseases of the skin. Haemangioma of the skin, of mucosae and of soft tissue
Humans
Ichthyosis - genetics
Life Sciences
Male
Medical sciences
Mutation
Photosensitivity Disorders - genetics
Transcription Factor TFIIH
Transcription Factors - genetics
Transcription Factors, TFII
Transcription, Genetic
Ultraviolet Rays
Xeroderma Pigmentosum - genetics
title A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy
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