Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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A gene, designated GS1, was identified by its association with a CpG island approximately 100 kb telomeric to the steroid sulfatase (STS) locus on the distal short arm of the human X chromosome. Both cDNA and genomic clones of the GS1 gene have been isolated and characterized. The cDNA clone detects a 2.3 kb transcript in human placenta and fibroblasts, and may encode a protein of 214 amino acid residues. Although sequences homologous to GS1 cDNA are present on chromosomes 1, 20, X, and Y, the functional GS1 gene is on the X chromosome. The GS1 gene appears to be non-essential, as there are no obvious clinical differences between STS deficient patients with point mutations in the STS gene, and patients with a deletion of the STS and GS1 genes. The GS1 gene is expressed from mouse-human cell hybrids containing active or inactive human X chromosomes, indicating that it escapes X inactivation. Characterization of GS1 genomic clones revealed that the gene consists of 4 exons spanning over 105 kb, with its transcriptional direction opposite to that of the STS gene. The isolation and characterization of a new gene which escapes X inactivation from distal Xp is of interest as it adds to our understanding of the structural organization of the human X chromosome and may help in providing clues regarding the mechanism of X-inactivation.
Hum Mol Genet 1992 Apr
PMID:Isolation of a new gene from the distal short arm of the human X chromosome that escapes X-inactivation. 128 67

Norrie disease is a human X-linked recessive disorder of unknown etiology characterized by congenital blindness, sensory neural deafness and mental retardation. This disease gene was previously linked to the DXS7 (L1.28) locus and the MAO genes in band Xp11.3. We report here fine physical mapping of the obligate region containing the Norrie disease gene (NDP) defined by a recombination and by the smallest submicroscopic chromosomal deletion associated with Norrie disease identified to date. Analysis, using in addition two overlapping YAC clones from this region, allowed orientation of the MAOA and MAOB genes in a 5'-3'-3'-5' configuration. A recombination event between a (GT)n polymorphism in intron 2 of the MAOB gene and the NDP locus, in a family previously reported to have a recombination between DXS7 and NDP, delineates a flanking marker telomeric to this disease gene. An anonymous DNA probe, dc12, present in one of the YACs and in a patient with a submicroscopic deletion which includes MAOA and MAOB but not L1.28, serves as a flanking marker centromeric to the disease gene. An Alu-PCR fragment from the right arm of the MAO YAC (YMAO.AluR) is not deleted in this patient and also delineates the centromeric extent of the obligate disease region. The apparent order of these loci is telomere ... DXS7-MAOA-MAOB-NDP-dc12-YMAO.AluR ... centromere. Together these data define the obligate region containing the NDP gene to a chromosomal segment less than 150 kb.
Hum Mol Genet 1992 May
PMID:The Norrie disease gene maps to a 150 kb region on chromosome Xp11.3. 130 Nov 61

A series of procedures including chromosome microdissection, sequence-independent PCR, Southern-blot-hybrid-selection-cloning and sequencing of microdissected DNA-library members were used to analyze DNA from a familial marker chromosome centromere and to determine the origin of the marker chromosome in the case of a live-born, tetraploid human infant. A new family of repetitive DNA, termed sn5 satellite, was sequenced and characterized by DNA hybridization. The sn5 satellite family appears to be primate-specific and shows a chromosome-specific distribution which parallels that of alpha satellite suprachromosomal family 2. This suprachromosomal classification is based on sequence similarity of centromeric alpha satellite DNA within particular groups of chromosomes. It has been postulated that the similarity of alphoid sequences within each of the three suprachromosomal families results from homologous exchanges between nonhomologous chromosomes within each family. The parallel distribution of sn5 satellite sequences at the centromeres of chromosomes of alphoid suprachromosomal family 2 suggests that homologous exchanges between non-homologous chromosomes may be the basis of simultaneous chromosome-specific sequence conservation for multiple centromeric satellite DNA families.
Hum Mol Genet 1992 Dec
PMID:Microdissection of a human marker chromosome reveals its origin and a new family of centromeric repetitive DNA. 130 4

Many disease loci have been linked to the telomeric end of the long arm of the human X-chromosome, Xq28. We have isolated and sequenced cDNA sequences corresponding to two novel genes that map to Xq28. These genes, c6.1A and c6.1B, are transcribed in opposite directions from a CpG island that lies approximately 70 kilobases (kb) upstream (5') of the factor VIII locus. One of these genes, c6.1A, is highly conserved between species and expressed abundantly in many human and mouse tissues, whereas, c6.1B is moderately conserved and has a restricted tissue distribution of expression. The Xq28 gene c6.1A has an autosomal homologue that is transcriptionally inactive in B-cell lines. An open reading frame (ORF) predicting a peptide of 293 amino acids is observed for c6.1A but c6.1B does not possess a single long ORF. No striking homologies to existing genes could be found for either of the two new loci. Expressed sequences that are physically close to the factor VIII gene are candidates for disease loci that map to this region of Xq28. The relevance of these genes to disease loci was investigated using DNA and RNA from hemophilia A patients bearing deletions that extend in a 5' direction away from factor VIII. The results imply that neither of these genes are primarily responsible for the development Xq28-linked diseases. However, c6.1A and c6.1B define a region of Xq28 that is deleted in two brothers that suffer from mental handicap and dysmorphism as well as hemophilia A. Thus, this region is likely to contain loci that are important for physical and mental development.
Hum Mol Genet 1992 Jun
PMID:Isolation and sequence of two genes associated with a CpG island 5' of the factor VIII gene. 130 75

Eight terminally deleted Drosophila melanogaster chromosomes have now been found to be "healed." In each case, the healed chromosome end had acquired sequence from the HeT DNA family, a complex family of repeated sequences found only in telomeric and pericentric heterochromatin. The sequences were apparently added by transposition events involving no sequence homology. We now report that the sequences transposed in healing these chromosomes identify a novel transposable element, HeT-A, which makes up a subset of the HeT DNA family. Addition of HeT-A elements to broken chromosome ends appears to be polar. The proximal junction between each element and the broken chromosome end is an oligo(A) tract beginning 54 nucleotides downstream from a conserved AATAAA sequence on the strand running 5' to 3' from the chromosome end. The distal (telomeric) ends of HeT-A elements are variably truncated; however, we have not yet been able to determine the extreme distal sequence of a complete element. Our analysis covers approximately 2,600 nucleotides of the HeT-A element, beginning with the oligo(A) tract at one end. Sequence homology is strong (greater than 75% between all elements studied). Sequence may be conserved for DNA structure rather than for protein coding; even the most recently transposed HeT-A elements lack significant open reading frames in the region studied. Instead, the elements exhibit conserved short-range sequence repeats and periodic long-range variation in base composition. These conserved features suggest that HeT-A elements, although transposable elements, may have a structural role in telomere organization or maintenance.
Mol Cell Biol 1992 Sep
PMID:HeT-A, a transposable element specifically involved in "healing" broken chromosome ends in Drosophila melanogaster. 132 9

The strong association of intratubular germ cell neoplasia (ITGCN) with adult germ cell testicular tumors is well known, but studies noting the absence of ITGCN in certain germ cell neoplasms such as spermatocytic seminoma, childhood teratoma, and infantile yolk sac tumor (YST) have raised the issue of whether these latter neoplasms follow a different path of tumorigenesis, accounting for their more benign behavior. A case study illustrating the association of ITGCN with infantile YST is presented to challenge this hypothesis. In addition to the usual characteristic features that included strong cytoplasmic glycogen deposits, and focal placental alkaline phosphatase immunoreactivity, the atypical intratubular germ cells manifested triploidy by in situ hybridization using as probe a telomeric tandem repeat sequence, p1-79, specific to chromosome 1. The invasive YST cells, in contrast, showed evidence of tetraploidy by both in situ hybridization and flow and image cytometric studies, excluding the possibility that the atypical intratubular germ cells represented intratubular invasion by adjacent YST. These findings challenge the belief that the infantile YST follows a different path of tumorigenesis than its adult germ cell counterpart and suggest other hypotheses that might better explain its more benign behavior.
Diagn Mol Pathol 1992 Jun
PMID:Intratubular germ cell neoplasia in infantile yolk sac tumor. Verification by tandem repeat sequence in situ hybridization. 134 58

We previously showed that the Uganda Palo Alto line of Plasmodium falciparum propagated in Saimiri monkeys and the line maintained in culture in human erythrocytes for many years in our laboratory are genetically unrelated (T. Fandeur, S. Bonnefoy, and O. Mercereau-Puijalon, Mol. Biochem. Parasitol. 47:167, 1991). When injected into a splenectomized Saimiri monkey, the in vitro-derived Palo Alto population procured a long-lasting, low-grade parasitemia that was spontaneously resolved by the animal. This line was propagated by serial blood transfers in two other monkeys without enhancement of the virulence of the parasites. The genetic characteristics of parasite samples corresponding to the different passages of the line in monkeys were stable for the several markers examined (pPF11.1, MSA1, and MSA2), although microheterogeneity was detected in telomeric and subtelomeric regions of chromosomes. Interestingly, in vitro-derived Palo Alto parasites induced a strong, potent immunity that enabled the monkeys to completely block subsequent challenge with two different heterologous lethal P. falciparum lines. These attenuated parasites are thus genetically stable in monkeys and represent an attractive model for assessing the feasibility of a live attenuated malaria vaccine.
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PMID:Protection of squirrel monkeys against virulent Plasmodium falciparum infections by use of attenuated parasites. 134 60

We have constructed a yeast artificial chromosome (YAC) library of tomato for chromosome walking that contains the equivalent of three haploid genomes (22,000 clones). The source of high molecular weight DNA was leaf protoplasts from the tomato cultivars VFNT cherry and Rio Grande-PtoR, which together contain loci encoding resistance to six pathogens of tomato. Approximately 11,000 YACs have been screened with RFLP markers that cosegregate with Tm-2a and Pto - loci conferring resistance to tobacco mosaic virus and Pseudomonas syringae pv. tomato, respectively. Five YACs were identified that hybridized to the markers and are therefore starting points for chromosome walks to these genes. A subset of the library was characterized for the presence of various repetitive sequences and YACs were identified that carried TGRI, a repeat clustered near the telomeres of most tomato chromosomes, TGRII, an interspersed repeat, and TGRIII, a repeat that occurs primarily at centromeric sites. Evaluation of the library for organellar sequences revealed that approximately 10% of the clones contain chloroplast sequences. Many of these YAC clones appear to contain the entire 155 kb tomato chloroplast genome. The tomato cultivars used in the library construction, in addition to carrying various disease resistance genes, also contain the wild-type alleles corresponding to most recessive mutations that have been mapped by classical linkage analysis. Thus, in addition to its utility for physical mapping and genome studies, this library should be useful for chromosome walking to genes corresponding to virtually any phenotype that can be scored in a segregating population.
Mol Gen Genet 1992 May
PMID:Construction of a yeast artificial chromosome library of tomato and identification of cloned segments linked to two disease resistance loci. 135 Dec 45

The expressed variant cell surface glycoprotein (VSG) gene of the protozoan parasite Trypanosoma brucei is invariably found at one of several telomeric VSG gene expression sites (ESs). The active ES in variant 118 clone 1 is found on a 1.5-Mb chromosome, and the promoter region is located more than 45 kb upstream of the VSG gene. We had previously shown that DNA rearrangement events occurred in the promoter region, specifically at inactivation of this ES (K. M. Gottesdiener, H.-M. Chung, S. L. Brown, M. G.-S. Lee, and L. H. T. Van der Ploeg, Mol. Cell. Biol. 11:2467-2477, 1991). In this report, we describe the cloning of the entire 17-kb promoter region, which revealed the presence of two identical 2.15-kb tandem promoter repeats separated by 13 kb of DNA. The two virtually identical promoter repeats both function efficiently in directing transcription in transient transfection assays in insect-form trypanosomes. We characterized the DNA rearrangement events that occur at ES inactivation, and by studying both of the reciprocal products of this recombination event, we infer that these result from direct (promoter) repeat recombination, formation of heteroduplex DNA, and a reciprocal exchange event that releases a circular DNA as a side product of the reaction. The finding of DNA recombinational events in a region of the VSG gene ES that encodes the promoter(s), and their relatively frequent occurrence at ES inactivation, suggests a possible role in ES control.
Mol Cell Biol 1992 Oct
PMID:A proposed mechanism for promoter-associated DNA rearrangement events at a variant surface glycoprotein gene expression site. 140 60

We have identified a DNA-binding activity with specificity for the TTAGGG repeat arrays found at mammalian telomeres. This factor, called TTAGGG repeat factor (TRF), is present in nuclear extracts of human, mouse, and monkey cells. TRF from HeLa cells was characterized in detail by electrophoretic mobility shift assays. It binds double-stranded TTAGGG repeats in linear and circular DNAs. Single-stranded repeats are not recognized. The optimal site for TRF appears to contain more than six contiguous TTAGGG repeats. Tandem arrays of TAGGG, TTTAGGG, TTTTAGGG, TTGGGG, and TTAGGC repeats do not bind TRF well, indicating that TRF preferentially recognizes the telomeric repeat sequence present at mammalian chromosome ends. The apparent molecular mass of this factor, based on recovery of TRF from sodium dodecyl sulfate-polyacrylamide gels, is approximately 50 kDa. We suggest that TRF binds along the length of mammalian telomeres.
Mol Cell Biol 1992 Nov
PMID:A mammalian factor that binds telomeric TTAGGG repeats in vitro. 140 65


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