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Biomedical subjects

A Gos

Publications and source records attributed to A Gos.

18 recordsLinked to original sources
PubMed1999

Isolation and characterization of the mouse Aire gene.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder characterized by Addison's disease and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. Patients may also have other clinical symptoms both within and outside the endocrine system, mainly as a result of autoimmunity against organ-specific autoantigens. The gene for APECED has recently been identified and termed AIRE (for AutoImmune REgulator). APECED is a model of organ-specific autoimmunity and isolation and characterization of the homologous mouse gene, Aire, will provide tools for dissection of the mechanisms underlying this human disorder and defining molecular pathways involved in organ-specific autoimmunity. We have isolated and completely sequenced the mouse Aire gene which is split into 14 exons over 13 kb and encodes a predicted protein of 552 amino acids. The predicted mouse and human AIRE proteins are 71% identical and contain motifs suggestive of a transcriptional regulator. Additional conserved motifs are emerging in the AIRE/Aire proteins including a nuclear localization signal, an "ASS" domain, and a "SAND" domain. The human and mouse AIRE promoters have conserved sites for several thymus-specific transcription factors and others important in hematopoesis, consistent with its expression in rare cells of the thymus medulla, lymph nodes, and fetal liver. We have mapped mouse Aire to mouse chromosome 10 by FISH, to the same region as Pwp2 and Pfkl, confirming synteny to the corresponding region of human chromosome 21.

3' Untranslated Regions↗
PubMed1999

A testis-specific gene, TPTE, encodes a putative transmembrane tyrosine phosphatase and maps to the pericentromeric region of human chromosomes 21 and 13, and to chromosomes 15, 22, and Y.

To contribute to the creation of a transcription map of human chromosome 21 (HC21) and to the identification of genes that may be involved in the pathogenesis of Down syndrome, exon trapping was performed from HC21-specific cosmids covering the entire chromosome. More than 700 exons have been identified to date. One such exon, hmc01a06, maps to YAC 831B6 which contains marker D21Z1 (alphoid repeats) and had previously been localized to the pericentromeric region of HC21. Northern-blot analysis revealed a 2.5-kb mRNA species strongly and exclusively expressed in the testis. We cloned the corresponding full-length cDNA, which encodes a predicted polypeptide of 551 amino acids with at least two potential transmembrane domains and a tyrosine phosphatase motif. The cDNA has sequence homology to chicken tensin, bovine auxilin and rat cyclin-G associated kinase (GAK). The entire polypeptide sequence also has significant homology to tumor suppressor PTEN/MMAC1 protein. We termed this novel gene/protein TPTE (transmembrane phosphatase with tensin homology). Polymerase chain reaction amplification, fluorescent in situ hybridization, Southern-blot and sequence analysis using monochromosomal somatic cell hybrids showed that this gene has highly homologous copies on HC13, 15, 22, and Y, in addition to its HC21 copy or copies. The estimated minimum number of copies of the TPTE gene in the haploid human genome is 7 in male and 6 in female. Zoo-blot analysis showed that TPTE is conserved between humans and other species. The biological function of the TPTE gene is presently unknown; however, its expression pattern, sequence homologies, and the presence of a potential tyrosine phosphatase domain suggest that it may be involved in signal transduction pathways of the endocrine or spermatogenetic function of the testis. It is also unknown whether all copies of TPTE are functional or whether some are pseudogenes. TPTE is, to our knowledge, the gene located closest to the human centromeric sequences.

Amino Acid Sequence↗
PubMed1998

Gene structure and chromosomal localization of the human P2X7 receptor.

The genomic organization for the human P2X7 receptor gene was determined to comprise 13 exons. Alignment of the exon-intron junctions with those for the rat P2X2 gene demonstrated a precise conservation of the boundaries for the first 10 introns. The human P2X7 receptor gene was localized by in situ hybridization to chromosome 12q24. Radiation hybrid mapping indicated that this is within 130 kb of the gene for the homologous P2X4 receptor.

Animals↗
PubMed1997

Familial translocation t(Y;15)(q12;p11) and de novo deletion of the Prader-Willi syndrome (PWS) critical region on 15q11-q13.

We describe a 17-year-old girl with mild Prader-Willi syndrome (PWS) due to 15q11-q13 deletion. The deletion occurred on a paternal chromosome 15 already involved in a translocation, t(Y;15)(q12;p11), the latter being present in five other, phenotypically normal individuals in three generations. This appears to be the first case of PWS in which the causative 15q11-q13 deletion occurred on a chromosome involved in a familial translocation, but with breakpoints considerably distal to those of the familial rearrangement. The translocation could predispose to additional rearrangements occurring during meiosis and/or mitosis or, alternatively, the association of two cytogenetic anomalies on the same chromosome could be fortuitous.

Adolescent↗
PubMed1997

Analysis of mutations and chromosomal localisation of the gene encoding RFX5, a novel transcription factor affected in major histocompatibility complex class II deficiency.

MHC class II deficiency is a severe primary immunodeficiency characterised by the absence of major histocompatibility complex class II (MHC-II) gene expression. It is genetically heterogeneous and can result from defects in at least four different trans-acting regulatory genes required for transcription of MHC-II genes. One of these genes has recently been shown to encode a novel DNA binding protein called RFX5, which is one subunit of a heteromeric protein complex (RFX) that binds to the promoters of MHC-II genes. We have characterised the mutations in all four patients known to harbour a defect in the RFX5 gene and have mapped this new human disease gene to chromosome 1 band q21, a region frequently exhibiting chromosomal aberrations in a variety of preneoplastic and neoplastic diseases.

Chromosome Mapping↗
PubMed1997

Fortuitous detection of uniparental isodisomy of chromosome 6.

Uniparental isodisomy is defined as the inheritance of two copies of the same parental chromosome and can result in defects when it produces homozygosity for a recessive mutation or in the presence of imprinting. We describe the detection of a chromosome 6 uniparental isodisomy in a 9 year old girl, discovered during a search for an HLA identical sib. HLA typing, erythrocyte phenotyping, and genotypes of microsatellite polymorphisms were compatible with a paternal isodisomy of chromosome 6, with normal biparental origin of the other chromosomes. Paternal cells were not responsive to the patient's cells in mixed lymphocyte cultures. This fortuitous detection of a chromosome 6 isodisomy suggests that cases of chromosome 6 UPD may not be deleterious and may therefore go undetected.

Cells, Cultured↗
PubMed1996

Localization of a human homolog of the mouse pericentrin gene (PCNT) to chromosome 21qter.

Exon trapping was used to identify portions of genes from cosmid DNA of a human chromosome 21-specific library LL21NC02-Q. More than 650 potential exons have been cloned and characterized to date. Among these, 3 trapped "exons" showed strong homology to different regions of the cDNA for the mouse pericentrin (Pcnt) gene (Doxsey et al., Cell 76: 639-650, 1994), indicating that these 3 exons are portions of a human homolog of the mouse pericentrin gene. With PCR amplification, Southern blot analysis, and FISH, we have mapped this presumed human pericentrin gene (PCNT) to the long arm of chromosome 21 between marker PFKL and 21qter. Pericentrin is a conserved protein component of the filamentous matrix of the centrosome involved in the initial establishment of the organized microtubule array. No candidate hereditary disorder for pericentrin deficiency/abnormality has yet been mapped in the most distal region of 21q; in addition the role of triplication of the pericentrin gene in the pathophysiology or etiology of trisomy 21 is currently unknown.

Amino Acid Sequence↗
PubMed1996

The gene for human U2 snRNP auxiliary factor small 35-kDa subunit (U2AF1) maps to the progressive myoclonus epilepsy (EPM1) critical region on chromosome 21q22.3.

We used targeted exon trapping to clone portions of genes from human chromosome 21q22.3. One trapped sequence showed complete homology with the cDNA of human U2AF35 (M96982; HGM-approved nomenclature U2AF1), which encodes for the small 35-kDa subunit of the U2 snRNP auxiliary factor. Using the U2AF1 cDNA as a probe, we mapped this gene to cosmid Q15D2, a P1, and YAC 350F7 of the Chumakov et al. (Nature 359: 380, 1992) contig, close to the cystathionine-beta-synthase gene (CBS) on 21q22.3. This localization was confirmed by PCR using oligonucleotides from the 3' UTR and by FISH. As U2AF1 associates with a number of different factors during mRNA splicing, overexpression in trisomy 21 individuals could contribute to some Down syndrome phenotypes by interfering with the splicing process. Furthermore, because this gene maps in the critical region for the progressive myoclonus epilepsy I locus (EPM1), mutation analysis will be carried out in patients to evaluate the potential role of U2AF1 as a candidate for EPM1.

Base Sequence↗
PubMed1996

Mapping of the gene for the p60 subunit of the human chromatin assembly factor (CAF1A) to the Down syndrome region of chromosome 21.

Exon trapping was used to clone portions of genes from the Down syndrome critical region (DSCR) of human chromosome 21. One trapped sequence showed complete homology with nucleotide sequence U20980 (GenBank), which corresponds to the gene for the p60 subunit of the human chromatin assembly factor-1 (CAF1A). We mapped this gene to human chromosome 21 by fluorescence in situ hybridization, by the use of somatic cell hybrids, and by hybridization to chromosome 21-specific YACs and cosmids. The CAF1A gene localizes to YACs 745H11 and 230E8 of the Chumakov et al. (1992, Nature 359: 380) YAC contig, within the DSCR on 21q22. This CAF1A, which belongs to the WD-motif family of genes and interacts with other polypeptide subunits to promote assembly of histones to replicating DNA, may contribute in a gene dosage-dependent manner to the phenotype of Down syndrome.

Animals↗
PubMed1995

Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11.

We report the results of two studies examining the genetic overlap between schizophrenia and velocardiofacial syndrome. In study A, we characterize two interstitial deletions identified on chromosome 22q11 in a sample of schizophrenic patients. The size of the deletions was estimated to be between 1.5 and 2 megabases. In study B, we examine whether variations in deletion size are associated with the schizophrenic phenotype in velocardiofacial syndrome patients. Our results show that a region of the genome that has been previously implicated by genetic linkage analysis can harbor genetic lesions that increase the susceptibility to schizophrenia. Our findings should facilitate identification and cloning of the schizophrenia susceptibility gene(s) in this region and identification of more homogeneous subgroups of patients.

Abnormalities, Multiple↗
PubMed1995

A new dinucleotide repeat polymorphism at the telomere of chromosome 21q reveals a significant difference between male and female rates of recombination.

We have used a half-YAC containing the human chromosome 21 long-arm telomere to clone, map, and characterize a new dinucleotide repeat polymorphism (D21S1575) close to 21qter. This marker is < 120 kb from the telomeric (TTAGGG)n sequences and is the most distal highly polymorphic marker on chromosome 21q. This marker has a heterozygosity of 71% because of a variable (TA)n repeat embedded within a long interspersed element (LINE) element. Genotyping of the CEPH families and linkage analysis provided a more accurate determination of the full length of the chromosome 21 genetic map. A highly significant difference was detected between male and female recombination rates in the telomeric region: in the most telomeric 2.3 Mb of chromosome 21q, recombination was only observed in male meioses.

Base Sequence↗
PubMed1995

Characterization and chromosomal localization of a human P2X receptor from the urinary bladder.

A cDNA encoding an ion channel (hP2X), gated by extracellular ATP, was isolated from the human urinary bladder. It encodes a 399 amino acid protein, composed of a cysteine-rich central domain, flanked by two hydrophobic regions. A comparison of the sequence with those of the corresponding rat and mouse proteins shows predominantly conservative substitutions of hydrophilic residues. Northern blot analysis demonstrated the presence of the mRNA in several human tissues and established that the distal untranslated portion of the mRNA includes an 'expressed sequence tag' for the differentiation of the hemopoetic cell line, HL60. By fluorescent in situ hybridization the hP2X gene was mapped to the short arm of human chromosome 17. Expressed in Xenopus oocytes, the receptor was sensitive to the purinergic agonists ATP and alpha,beta-methylene ATP.

Amino Acid Sequence↗
PubMed1992

Polarized secretion of urokinase-type plasminogen activator by epithelial cells.

Numerous epithelial cell types produce and secrete plasminogen activators (PAs) and/or PA inhibitors (PAIs). When epithelial cells were grown on polycarbonate filters and their apical and basolateral secretion products analyzed, PA activity accumulated in a highly polarized fashion; depending upon the cell line, the compartment of PA accumulation was either apical (MDCK I cells and HBL-100 cells) or basolateral (LLC-PK1, CaCo-2, and HeLa cells). By contrast, PAI-1 was recovered in roughly equal amounts in both compartments. Basolateral accumulation of urokinase-type plasminogen activator (uPA), but not its apical targeting, required an acidic compartment and the integrity of the cytoskeleton. Polarity of uPA accumulation did not result from removal of the free enzyme from the opposite compartment through its binding to the cell surface. Transfection with wild-type or mutated murine uPA demonstrated that neither the "growth factor" domain nor the kringle domain is required for the appropriate sorting of the protein. We propose that polarized secretion of PAs is one mechanism whereby cells spatially control extracellular proteolysis.

Ammonium Chloride↗