Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A genetic linkage map of human chromosome 9q, spanning a sex-equal distance of 125 cM, has been developed by genotyping 26 loci in the Venezuelan Reference Pedigree. The loci include 12 anonymous microsatellite markers reported by Kwiatkowski et al. (1992), several classical systems previously assigned to chromosome 9q, and polymorphisms for the genes tenacin (HXB), gelsolin (GSN), adenylate kinase 1 (AK1), arginosuccinate synthetase (ASS), ABL oncogene (ABL1), ABO blood group (ABO), and dopamine beta-hydroxylase (DBH). Only a marginally significant sex difference is found along the entire length of the map and results from one interval, between D9S58 and D9S59, that displays an excess of female recombination. A comparison of the genetic map to the existing physical data suggests that there is increased recombination in the 9q34 region with a recombination event occurring every 125-400 kb. This map should be useful in further characterizing the relationship between physical distance and genetic distance, as well as for genetic linkage studies of diseases that map to chromosome 9q, including multiple self-healing squamous epithelioma (MSSE), Gorlin syndrome (NBCCS), xeroderma pigmentosum (XPA), nail-patella syndrome (NPS1), torsion dystonia (DYT1), and tuberous sclerosis (TSC1).
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PMID:A genetic linkage map of human chromosome 9q. 142 99

Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) is an autosomal dominant disorder, characterized primarily by multiple basal cell carcinomas, epithelium-lined jaw cysts, and palmar and plantar pits, as well as various other features. Loss of heterozygosity studies and linkage analysis have mapped the NBCCS gene to chromosome 9q and suggested that it is a tumor suppressor. The apparent sensitivity of NBCCS patients to UV and X-irradiation raises the possibility of hypersensitivity to DNA-damaging reagents or defective DNA repair being etiological in the disorder. The recent mapping of the Fanconi anaemia group C (FACC) and xeroderma pigmentosum complementing group A (XPAC) genes to the same region on 9q has led us to begin the molecular dissection of the 9q22-q31 region. PCR analysis of the presence or absence of 10 microsatellite markers and exons 3 and 4 of the XPAC and FACC genes, respectively, allowed us to order 12 YACs into an overlapping contig and to order the markers as follows: D9S151/D9S12P1-D9S12P2-D9S197-D9S196-D9 S280-FACC-D9S287/XPAC-D9S180-D9S6-D9 S176 . Sizing of the YACs has provided an initial estimate of the size of the NBCCS candidate region between D9S12 and D9S180 to be less than 1.65 Mb.
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PMID:A YAC contig spanning the nevoid basal cell carcinoma syndrome, Fanconi anaemia group C, and xeroderma pigmentosum group A loci on chromosome 9q. 782 76

Gorlin syndrome is an autosomal dominant disorder characterized by multiple basal cell carcinomas, medulloblastomas, ovarian fibromas, and a variety of developmental defects. All affected individuals share certain key features, but there is significant phenotypic variability within and among kindreds with respect to malformations. The gene (NBCCS) maps to chromosome 9q22, and allelic loss at this location is common in tumors from Gorlin syndrome patients. Two recessive cancer-predisposition syndromes, xeroderma pigmentosum group A (XPAC) and Fanconi anemia group C (FACC), map to the NBCCS region; and unusual, dominant mutations in these genes have been proposed as the cause of Gorlin syndrome. This study presents cytogenetic and molecular characterization of germ-line deletions in one patient with a chromosome 9q22 deletion and in a second patient with a deletion of 9q22-q3l. Both have typical features of Gorlin syndrome plus additional findings, including mental retardation, conductive hearing loss, and failure to thrive. That Gorlin syndrome can be caused by null mutations (deletions) rather than by activating mutations has several implications. First, in conjunction with previous analyses of allelic loss in tumors, this study provides evidence that associated neoplasms arise with homozygous inactivation of the gene. In addition, dominant mutations of the XPAC and FACC1 genes can be ruled out as the cause of Gorlin syndrome, since the two patients described have null mutations. Finally, phenotypic features that show variable expression must be influenced by genetic background, epigenetic effects, somatic mutations, or environmental factors, since these two patients with identical alterations (deletions) of the Gorlin syndrome gene have somewhat different manifestations of Gorlin syndrome.
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PMID:Molecular analysis of chromosome 9q deletions in two Gorlin syndrome patients. 875 29

The MSSE gene predisposes to the development of multiple invasive but self-healing skin tumours (multiple self-healing squamous epitheliomata, MSSE). MSSE (previously named ESS1) was mapped to chromosome 9q by linkage analysis; haplotype analysis in families then suggested a common founder mutation and indicated that the gene lies in the interval D9S1-D9S29 (9q22-q31). Squamous cell carcinomata also develop as one of the complications of xeroderma pigmentosum, and one of the xeroderma pigmentosum genes (XPA) maps within the MSSE interval. We have investigated the hypothesis that a novel dominant mutation in XPA is responsible for MSSE. We screened the entire coding region, 3' untranslated region (UTR) and 5'UTR of XPA for germline mutations in MSSE families by single-stranded conformation polymorphism analysis and by direct DNA sequencing. No mutations were detected but a novel intragenic polymorphism was identified in the 5'UTR of XPA, in both MSSE-affected and unrelated normal individuals. This XPA polymorphism and nine new polymorphic markers that map in the MSSE region were typed in eleven MSSE families; XPA was excluded as the MSSE gene and the most likely location of MSSE was reduced to the interval between D9S197 and (D9S287, D9S1809). The Patched (PTCH) gene, which is mutated in naevoid basal cell carcinoma syndrome (NBCCS or Gorlin syndrome) lies in this interval and all MSSE families have been shown to share a common haplotype at three novel intragenic PTCH polymorphisms. Although no mutation has been detected in MSSE families, PTCH has not been excluded as the MSSE gene.
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PMID:Mapping the multiple self-healing squamous epithelioma (MSSE) gene and investigation of xeroderma pigmentosum group A (XPA) and PATCHED (PTCH) as candidate genes. 943 61

The human homologue of Drosophila patched (PTCH), located at chromosome 9q22.3, was recently identified as a candidate tumor suppressor gene for familial and sporadic basal cell carcinomas. Squamous cell carcinomas (SCCs) of the skin display allelic loss in this chromosomal region, which, in addition to the PTCH gene, contains the DNA repair gene xeroderma pigmentosum complementation group A (XPA). Patients with xeroderma pigmentosum are predisposed to non-melanoma skin tumors because of deficient excision repair of ultraviolet-induced DNA damage. Mutation analysis by single-strand conformation analysis and direct DNA sequencing of all 23 exons of the PTCH gene and all six exons of the XPA gene in 14 SCCs did not reveal structural alterations in any of these genes. Additionally, analysis of PTCH expression by in situ hybridization in SCCs revealed no evidence of upregulation of PTCH mRNA, confirming the lack of mutations in this gene. These findings suggest that another, yet to be identified gene or genes on chromosome 9q are involved in SCC tumorigenesis.
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PMID:Mutation analysis of the human homologue of Drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin. 949 8

Recently, hptc, a human gene homologous to the Drosophila segment polarity gene patched (ptc), has been implicated in the nevoid basal-cell carcinoma (BCC) syndrome, and somatic mutations of hptc also have been found in sporadic BCCs, the most frequent cancers found in the white population. We have analyzed the hptc gene, postulated to be a tumor suppressor gene, in 22 BCCs from patients with the hyperphotosensitive genodermatosis xeroderma pigmentosum (XP). Patients with XP are deficient in the repair of UV-induced DNA lesions and are characterized by their predisposition to cancers in sun-exposed skin. Analysis using PCR-single-strand conformation polymorphism of the hptc gene identified 19 alterations in 16 of 22 (73%) of the BCCs examined. Only two (11%) deletions of the hptc gene were found in XP BCCs compared with >30% rearrangement observed in non-XP sporadic BCCs, and 17 of 19 (89%) were base substitutions. Among the 17 base substitutions, 11 (65%) were CC --> TT tandem mutations, and 4 (23%) were C --> T substitutions, all targeted at bipyrimidine sites. Hence, a significantly higher number (15 of 19; 79%) of UV-specific alterations are seen in XP tumors, in contrast to non-XP sporadic BCCs. Interestingly, we have found that in 7 of 14 (50%) XP BCCs analyzed, both hptc and the tumor suppressor gene p53 are mutated. Not only have our data indicated the key role played by hptc in the development of BCCs, they also have substantiated the link between unrepaired UV-induced DNA lesions and skin carcinogenesis, as exemplified by the UV-specific alterations of different genes in the same tumors.
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PMID:High levels of patched gene mutations in basal-cell carcinomas from patients with xeroderma pigmentosum. 1022 Apr 28

Molecular analysis of p53 and patched (PTCH), two candidate tumor suppressor genes for non-melanocytic skin cancer, was performed in skin tumors from six patients affected by the cancer-prone disease xeroderma pigmentosum (XP). UV-specific p53 mutations were detected at a frequency of 38-50% in all the tumor types analysed, including melanomas. Additional analysis of PTCH mutations in the subset of eight basal call carcinomas (BCC) revealed a very high mutation frequency of this gene (90%) which exceeded that detected in the p53 gene in the same tumors (38%). PTCH mutations were predominantly UV-specific C>T transitions. This mutation pattern is different from that reported in BCC from normal donors where PTCH mutation frequency is 27% and mutations are frequently deletions and insertions. These findings suggest that PTCH mutations represent an earlier event in BCC development than p53 alterations and that the inability of XP patients to repair UV-induced PTCH mutations might significantly contribute to the early and frequent appearance of BCC observed in these patients.
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PMID:UV mutation signature in tumor suppressor genes involved in skin carcinogenesis in xeroderma pigmentosum patients. 1065 95

Germline mutations of the human patched gene, PTCH, are responsible for the nevoid basal cell carcinoma (NBCC) syndrome or Gorlin's syndrome, characterized by multiple skin cancers, internal cancers and severe developmental abnormalities. The patched gene codes for a developmental regulator protein implicated in the sonic hedgehog (SHH) signalling pathway which plays an important role in oncogenic transformation. Patched exhibits tumor suppression function and has been shown to be mutated in skin cancers isolated from DNA repair-proficient patients or from xeroderma pigmentosum (XP), a DNA repair-deficient syndrome. We have reviewed and analyzed in detail the different mutation spectra found on the PTCH gene in these various models. The type and distribution of mutations are quite different between germline, sporadic and XP cancers. Among the germline alterations, there is a preponderance (70%) of rearrangements compared to other tumour types analysed where less than 30% of rearrangements is observed. Typical UV-induced mutations of the patched gene are found prominently in XP basal cell carcinomas (BCCs) and in particular, a significantly higher level (63%) of the UV signature tandem mutations is found compared to sporadic BCC (11%). The location of mutations along the PTCH protein delineates several important functional domains implicated in the biology of this transmembrane receptor.
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PMID:UV-specific mutations of the human patched gene in basal cell carcinomas from normal individuals and xeroderma pigmentosum patients. 1083 43

Basal cell carcinoma (BCC) of the skin is the most common type of cancer in humans. Like squamous cell carcinomas, they are also believed to be ultraviolet (UV)-induced, but several data suggest that some differences might exist in the mechanisms of their UV induction. The originating cells may arise from interfollicular basal cells, hair follicles or sebaceous glands, thus from a deeper zone than the SCC ones, which probably means exposure to different doses or wavelengths of UV. The p53 gene and the patched gene (PTCH) are major targets of UV for BCC induction. Mutations in p53 are present in about 56% of human BCC, even small early lesions. The "UV signature" is observed in 65% of them. Mutations in the PTCH play also a major role in BCC development, being responsible for hereditary BCCs in Gorlin's syndrome, sporadic BCC, and BCCs isolated from xeroderma pigmentosum, although with a lower incidence of "UV signature". Smoothened-activating mutations and PTCH2 mutations are also involved in BCC formation. Transgenic mice overexpressing Smoothened or Sonic hedgehog in the skin spontaneously produce skin lesions resembling human BCCs, but contrary to findings in the hairless albino mouse and with SCC, no data on experimental UV induction of BCCs are available.
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PMID:Carcinogenesis of basal cell carcinomas: genetics and molecular mechanisms. 1196 27

The Sonic hedgehog (SHH) pathway is implicated in the etiology of the most common human cancer in Caucasians, the basal cell carcinoma (BCC). Mutations in the receptor of SHH, the patched gene, have been characterized in sporadic BCCs as well as those from patients with the rare genetic syndromes nevoid BCC and xeroderma pigmentosum (XP). To elucidate the role of UV in the deregulation of the SHH pathway, we analyzed for alterations of smoothened, a transmembrane signaling component regulated by patched, in BCCs and squamous cell carcinomas from UV hypersensitive XP patients. We find UV-specific smoothened mutations in 30% of XP BCCs, three times higher than those in sporadic Caucasian BCCs, confirming the high rate of UV-induced mutations in DNA repair-deficient XP patients. No alteration was found in XP squamous cell carcinomas, indicating the involvement of smoothened specifically in the development of BCC.
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PMID:Significantly high levels of ultraviolet-specific mutations in the smoothened gene in basal cell carcinomas from DNA repair-deficient xeroderma pigmentosum patients. 1249 55


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