Xp Genes Research Articles

Assessment of Nucleotide Excision Repair XPD Polymorphisms in the Peripheral Blood of Gemcitabine/Cisplatin–Treated Advanced Non–Small-Cell Lung Cancer Patients

Only about one third of non—small-cell lung cancer (NSCLC) patients respond to cisplatin-based chemotherapy. Cisplatin DNA adducts are commonly repaired through the nucleotide excision repair pathway. The study of rare inherited disorders such as xeroderma pigmentosum and Cockayne syndrome has disclosed that XP genes, including XPD, play an essential role in DNA repair, both in the global genomic repair and in the transcription-coupled repair pathways. XPD polymorphism and decreased expression of XP genes have both been linked to lower DNA repair capacity. ERCC1 overexpression has been associated with cisplatin resistance, and experimental evidence shows a close association between ERCC1 and XPD. In the present study, we have examined XPD polymorphisms at codons 751 and 312 in DNA isolated from peripheral blood in 39 patients with gemcitabine/cisplatin—treated locally advanced non-small-cell lung cancer. Although no significant correlation was observed between XPD genotype and objective response, a trend toward better response was observed in patients with XPD polymorphism at codon 312. The map of the nucleotide excision repair pathway can be used to design translational research studies to identify and validate predictive markers of response to cisplatin, and the Spanish Lung Cancer Group has recently accrued 250 gemcitabine/cisplatin—treated NSCLC patients for a prospective assessment of XPD genotype.

In Brief

Because of its compactness, the genome of Tetraodon nigroviridis (freshwater pufferfish) has been described as an ideal reference to identify and validate vertebrate genes. Using fluorescence in situ hybridization (FISH), scientists under the leadership of Thomas Haaf have mapped genes from human chromosome X to those in the pufferfish. The results demonstrate that the human X chromosome is a mosaic of three pufferfish chromosomes. More than 350 million years ago, an ancestral vertebrate shared orthologous Xp and Xq genes with Tetraodon chromosomes 1 and 7; the third chromosomal addition appears to be more recent. The authors propose that before its conversion into a mammalian sex chromosome, the X chromosome underwent a highly specialized evolutionary selection procedure to generate the highly conserved gene arrays, followed by the recruitment of genes for reproduction and/or the development of cognitive abilities. (Grutzner, F. et al. [2002] Genome Res. 12, 1316–1322) SG

Molecular analysis of genes on Xp controlling Turner syndrome and premature ovarian failure (POF).

Monosomy X has been known to be the chromosomal basis of Turner syndrome (TS) for more than four decades. A large body of cytogenetic data indicates that most TS features are due to reduced dosage of genes on the short arm of the X chromosome (Xp). Phenotype mapping studies using molecular cytogenetic and genetic techniques are beginning to localize the Xp genes that are important for various TS features, and a comprehensive catalog of candidate genes is becoming available through the Human Genome Project and related research. It is now possible to assess the contributions of individual genes to the TS phenotype by mutational analysis of karyotypically normal persons with specific TS features. This strategy has succeeded in identifying a gene involved in short stature and is being applied to premature ovarian failure and other TS phenotypes.

Repair of mtDNA in Vertebrates

The author's research is supported by National Institutes of Health grants GM29681 and ES04068.

CSF2RA, ANT3, and STS are autosomal in marsupials: implications for the origin of the pseudoautosomal region of mammalian sex chromosomes.

The X and Y Chromosomes (Chrs) of eutherian ("placental") mammals share a pseudo-autosomal region (PAR) that pairs and recombines at meiosis. In humans and other eutherians, the PAR contains several active genes and has also been thought to be critical for pairing and fertility. In order to explore the origin of the PAR, we cloned and mapped three human or mouse pseudoautosomal genes in marsupials, a group of mammals that diverged from eutherians about 130 (MYrBP). All three genes were autosomal in marsupials, and two co-localized with other human Xp genes on an autosome. This implies that the human PAR, like most of human Xp, represents a relic of an autosomal region added to both X and Y Chrs between 80 and 150 MYrBP.

The Candidate Sex-ReversingDAX1Gene Is Autosomal in Marsupials: Implications for the Evolution of Sex Determination in Mammals

The human X-linkedDAX1gene was cloned from the region of the short arm of the human X found in duplicate in sex-reversed XdupY females (E. Zanariaet al.,1994,Nature372: 635–641).DAX1is suggested to be required for ovarian differentiation and to play an important role in mammalian sex determination or differentiation pathways. Its proposed dose-dependent effect on sexual development suggests thatDAX1could represent an evolutionary link with an ancestral sex-determining mechanism that depended on the dosage of an X-linked gene. Furthermore,DAX1could also represent the putative X-linked switch gene, which independently controls sexual dimorphisms in marsupial mammals in an X-dose-dependent manner (D. W. Cooperet al.,1993,Semin. Dev.4: 117–128). IfDAX1has a present role in marsupial sexual differentiation or had an ancestral role in mammalian sex determination, it would be expected to lie on the marsupial X chromosome, despite the autosomal localization of other human Xp genes. We therefore cloned and mapped theDAX1gene in the tammar wallaby (Macropus eugenii).DAX1was located on wallaby chromosome 5p near other human Xp genes, indicating that it was originally autosomal and that it is not involved in X-linked dose-dependent sex determination in an ancestral mammal nor in marsupial sexual differentiation.

XX true hermaphroditism in southern African blacks: exclusion of SRY sequences and uniparental disomy of the X chromosome.

A molecular investigation of 16 Bantu-speaking Black XX true hermaphrodites was undertaken in an attempt to determine the cause of the disorder. Y-specific sequences, including sequences mapping to the sex-determining region of the Y, were shown to be absent from lymphocyte tissue of all 16 patients tested. Y chromosome sequences were also absent from the ovarian and testicular components of both ovotestes of a single XX true hermaphrodite, thus excluding gonadal mosaicism involving Y chromosome sequences. Since there is evidence for Xp genes involved in testis determination/differentiation, uniparental disomy of the X chromosome was investigated in 14 XXTH families. Uniparental disomy was excluded in 12 of the 14 families, and isodisomy was excluded in the remaining two cases.

The glycerol kinase gene family: structure of the Xp gene, and related intronless retroposons.

The human glycerol kinase gene family consists of at least six genomic loci, four of which encode expressed sequences. The X-linked gene responsible for GKD maps to Xp21.3. Analysis of cosmid and YAC clones shows that this locus is in excess of 50 kbp, and is comprised of 19 exons. In contrast, the remaining members of the gene family, on chromosomes 1, 4 and Xq, appear to be organized as intronless genes. Northern analysis shows expression of GK transcripts of three sizes in a wide range of adult tissues. Only the smallest hybridizing species is present in testis where it occurs at an elevated level. Two different testis transcripts have been identified and both of these originate from chromosome 4.

Mapping human X-linked genes in the phalangerid marsupial Trichosurus vulpecula

We mapped 15 human X-chromosome markers in the common brush-tailed possum, Trichosurus vulpecula (Kerr), which represents the Australian marsupial family Phalangeridae. In situ hybridization was used to localize highly conserved human X-linked genes to chromosomes of T. vulpecula diploid lines. Ten genes located on the long arm of the human X (human Xq genes) all mapped to the possum X chromosome. However, all five genes located on the short arm of the human X (human Xp genes) mapped to autosomes. These findings confirm our previous work, which showed that the X chromosome in macropodid and dasyurid marsupials bears all the human Xq genes but none of the human Xp genes studied. This suggests that the marsupial X is highly conserved, but its gene content reflects that of only part of the eutherian X, a result consistent with our hypothesis that an autosomal region was added to the X early in eutherian divergence.

Exocrine Pancreas Transcription Factor 1 Binds to a Bipartite Enhancer Element and Activates Transcription of Acinar Genes

Exocrine pancreas (XP) enhancers, which contain a conserved core sequence, are active only in XP cells. A core enhancer-binding activity also appears to be restricted to XP nuclei. Here we describe the properties of a factor, purified approximately 100,000-fold from pancreas nuclei, which displays core enhancer-binding activity. It is not identical to previously characterized factors and is termed exocrine pancreas transcription factor 1 (XPF-1). In the highly purified preparation, only a single major protein of 60 kDa was detected by silver staining on sodium dodecyl sulfate-gels and by UV cross-linking. XPF-1 binds to the core enhancer of all tested XP genes and not to a mutant sequence which is inactive in vivo. High-affinity binding sites are bipartite. The results of competition binding and UV-cross-linking assays suggest that XPF-1 interacts with both motifs. XPF-1 selectively stimulates transcription of core enhancer templates in an in vitro transcription system. We hypothesize that XPF-1 plays a role in activation of the transcription of XP-specific genes.

Genes on the short arm of the human X chromosome are not shared with the marsupial X

Eight genes located on the short arm of the human X chromosome (MAOA, SYN1, OAT, OTC, CYBB, DMD, ZFX, POLA) have been mapped in several marsupial species by cell hybrid analysis and/or in situ hybridization using probes derived from human cDNA. Seven appear to be autosomal in all marsupial species examined. The eighth, CYBB, detected a site on the X, as well as major autosomal sites. Although these genes are not conserved on the X chromosome in marsupials, at least some of them are arranged together in autosomal clusters. The autosomal location of human Xp genes in marsupials could mean that this region either was lost from a large ancestral X chromosome in the marsupial lineage or was acquired by a small ancestral X (and perhaps Y) in the eutherian lineage. Either explanation demands that the region was not subject to X chromosome inactivation in a common ancestor 120–150 MyrBP.

Exocrine pancreas transcription factor 1 binds to a bipartite enhancer element and activates transcription of acinar genes.

Exocrine pancreas (XP) enhancers, which contain a conserved core sequence, are active only in XP cells. A core enhancer-binding activity also appears to be restricted to XP nuclei. Here we describe the properties of a factor, purified approximately 100,000-fold from pancreas nuclei, which displays core enhancer-binding activity. It is not identical to previously characterized factors and is termed exocrine pancreas transcription factor 1 (XPF-1). In the highly purified preparation, only a single major protein of 60 kDa was detected by silver staining on sodium dodecyl sulfate-gels and by UV cross-linking. XPF-1 binds to the core enhancer of all tested XP genes and not to a mutant sequence which is inactive in vivo. High-affinity binding sites are bipartite. The results of competition binding and UV-cross-linking assays suggest that XPF-1 interacts with both motifs. XPF-1 selectively stimulates transcription of core enhancer templates in an in vitro transcription system. We hypothesize that XPF-1 plays a role in activation of the transcription of XP-specific genes.

An interstitial deletion in Xp22.3 in a family with X-linked recessive chondrodysplasia punctata and short stature

In a four-generation family, chondrodysplasia punctata was found in a boy and one of his maternal uncles. These two patients also have short stature, as do all female members of the family, DNA molecular analysis of the pseudoautosomal and Xp22.3-specific loci revealed the presence of an interstitial deletion that cosegregates with the phenotypic abnormalities. The proximal breakpoint of this deletion was located distal to the DXS31 locus and the distal breakpoint in the pseudoautosomal region between DXYS59 and DXYS17. This maps the recessive X-linked form of chondrodysplasia punctata between the proximal boundary of the pseudoautosomal region and DXS31, and an Xp gene controlling growth between DXYS59 and DXS31.

Involvement of MHC‐Linked Hemopoietic‐Histocompatibility Genes in Allogeneic Bone Marrow Transplantation in Mice

Genes controlling resistance of irradiated mice of allogeneic hemopoietic cells were mapped within, or closely linked to the D region of MHC and were designated Hemopoietic-histocompatibility genes (Hha). Hhp genes responsible for resistance to parenteral hemopoietic cells had also previously been detected on the D-end of MHC. Hh genes are regarded as determinants of cell surface antigens (Hh antigens) phenotypically expressed, in contrast to Histocompatibility antigens (H antigens) only on blood-forming and leukemic cells. The inheritance of Hh genes is not codominant, unlike thformed on peripheral blood lymphocytes and platelets. Sixteen Tunisian families were typed with 37 patients and 108 relatives. Genetic transmission of the disease of the HLA system seemed to be independent in this study. Comparison of HLA gene frequencies (unrelated) parents of patients and a control population showed no difference, proving that there is no clear association in population between deleterious XP genes and a particular HLA gene. However, an excess of identical HLA among pairs of diseased siblings would suggest that the disease is polymorphic and a form of the XP could be linked to HLA.

HLA antigens in 16 families with xeroderma pigmentosum.

Xeroderma pigmentosum is an autosomal recessive disease. HLA-A and -B typing was performed on peripheral blood lymphocytes and platelets. Sixteen Tunisian families were typed with 37 patients and 108 relatives. Genetic transmission of the disease and of the HLA system seemed to be independent in this study. Comparison of HLA gene frequencies between (unrelated) parents of patients and a control population showed no difference, proving that there is no clear association in populations between deleterious XP genes and a particular HLA gene. However, an excess of identical HLA among pairs of diseased siblings would suggest that the disease is polymorphic and a form of the XP could be linked to HLA.