Clinical heterogeneity within xeroderma pigmentosum associated with mutations in the DNA repair and transcription gene ERCC3

Journal Article · Tue Feb 01 04:00:00 EST 1994 · American Journal of Human Genetics; (United States)

OSTI ID:7160652

Vermeulen, W; Kleijer, W J; Bootsma, D; Hoeijmakers, J H.J.; Weeda, G ^[1]; Scott, R J; Rodgers, S; Mueller, H J ^[2]; Cole, J; Arlett, C F ^[3]

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1. Erasmus Univ., Rotterdam (Netherlands)
2. Univ. Hospital, Basel (Switzerland)
3. Univ. of Sussex, Brighton (United Kingdom)

The human DNA excision repair gene ERCC3 specifically corrects the nucleotide excision repair (NER) defect of xeroderma pigmentosum (XP) complementation group B. In addition to its function in NER, the ERCC3 DNA helicase was recently identified as one of the components of the human BTF2/TFIIH transcription factor complex, which is required for initiation of transcription of class II genes. To date, a single patient (XP11BE) has been assigned to this XP group B (XP-B), with the remarkable conjunction of two autosomal recessive DNA repair deficiency disorders: XP and Cockayne syndrome (CS). The intriguing involvement of the ERCC3 protein in the vital process of transcription may provide an explanation for the rarity, severity, and wide spectrum of clinical features in this complementation group. Here the authors report the identification of two new XP-B patients: XPCS1BA and XPCS2BA (siblings), by microneedle injection of the cloned ERCC3 repair gene as well as by cell hybridization. Molecular analysis of the ERCC3 gene in both patients revealed a single base substitution causing a missense mutation in a region that is completely conserved in yeast, Drosophila, mouse, and human ERCC3. As in patient XP11BE, the expression of only one allele (paternal) is detected. The mutation causes a virtually complete inactivation of the NER function of the protein. Despite this severe NER defect, both patients display a late onset of neurologic impairment, mild cutaneous symptoms, and a striking absence of skin tumors even at an age of >40 years. Analysis of the frequency of hprt[sup [minus]] mutant T-lymphocytes in blood samples suggests a relatively low in vivo mutation frequency in these patients. Factors in addition to NER deficiency may be required for the development of cutaneous tumors. 43 refs., 6 figs., 2 tabs.

• OSTI ID: 7160652
• Journal Information: American Journal of Human Genetics; (United States), Journal Name: American Journal of Human Genetics; (United States) Vol. 54:2; ISSN AJHGAG; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

550400* -- Genetics
59 BASIC BIOLOGICAL SCIENCES
BIOLOGICAL RECOVERY
BIOLOGICAL REPAIR
CONGENITAL DISEASES
DISEASES
DNA REPAIR
EXCISION REPAIR
GENE MUTATIONS
HEREDITARY DISEASES
INACTIVATION
MUTATIONS
REPAIR
SKIN DISEASES
TRANSCRIPTION FACTORS
XERODERMA PIGMENTOSUM