Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chromosome analysis in a 31-year-old woman referred for primary amenorrhea, revealed a very high incidence of chromosome aberrations. She had microcephaly and immunodeficiency. Her healthy parents were consanguineous (1/32) and a younger sister, also with primary amenorrhea, died when 20 years old with a malignant lymphoma. Chromosome studies were performed on lymphocytes and fibroblasts and in both tissues a high proportion of metaphases with multiple chromosome aberrations was found. Clonal and sporadic rearrangements, consisting of balanced and unbalanced translocations and dicentric chromosomes were more numerous than chromatid and chromosome breaks. In the lymphocytes the same unbalanced translocation t(8q;21q) was present in about 59% of the metaphases. Rearrangements involving chromosomes 7 and 14, similar to those described in patients with ataxia-telangiectasia were found, but with a lower frequency. Sister Chromatid Exchanges were not increased. Chromosome and chromatid abnormalities were enhanced after exposure of cells to mitomycin C but not after exposure to the radiomimetic drug bleomycin. Clinical and cytogenetic characteristics of the patient are compared with those of syndromes (Ataxia-Telangiectasia and Werner's syndrome) or isolated cases (Weemaes et al. 1981, Sperling 1983, Spinner et al. 1985) whose features are similar to those of our patient. This case might represent a new chromosome instability syndrome due to a recessive mutation.
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PMID:A new chromosome instability disorder. 380 54

A cellular immunodeficiency was revealed in a 39-year-old female patient suffering from Werner's syndrome. Relevant findings were negative intracutaneous tests to candidin, trichophytin, tuberculin and bacterial antigens, reduced lymphocyte response to PHA, and impaired intracellular killing of Candida albicans by granulocytes. The inclination of patients suffering from Werner's syndrome to develop neoplasms may be related to this immunodeficiency.
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PMID:Altered cellular immunity in Werner's syndrome. 699 96

Ataxia-telangiectasia (A-T) is a recessive human disease characterized by radiation sensitivity, genetic instability, immunodeficiency, and high cancer risk. We previously used expression cloning to identify CAT4.5, a human cDNA that partially suppresses multiple aspects of the A-T phenotype upon transfection into cultured cells. Sequencing CAT4.5 revealed a 1.1-kb intronic fragment followed by a related ORF of 2.5 kb that encodes the near full-length ORF for hTOP3, the first mammalian topoisomerase III to be identified. Endogenous expression of hTOP3 was found in all human tissues tested. Both pCAT4.5 and an antisense hTOP3 construct were able to inhibit spontaneous and radiation-induced apoptosis in A-T fibroblasts, whereas overexpression of a full-length hTOP3 cDNA did not. We postulate that topoisomerase III may be deregulated in A-T cells and that CAT4.5 complements the A-T phenotype via a dominant-negative mechanism. Furthermore, functional correction of hyper-recombination in A-T cells by CAT4.5 supports the hypothesis that the hTOP3 topoisomerase is involved in the control of genomic stability, perhaps in concert with the Bloom or Werner syndrome DNA helicases.
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PMID:Overexpression of a truncated human topoisomerase III partially corrects multiple aspects of the ataxia-telangiectasia phenotype. 911 25

Soft tissue sarcoma (STS) accounts for approximately 1% of all cancers diagnosed annually in the United States. Population-based data from Connecticut covering the years 1935-1989 have shown an increasing incidence of STS in both genders, with a greater increase among men than women. The recent increase in acquired immune deficiency syndrome-related Kaposi's sarcoma does not explain the upward trend in STS, dating back decades. Etiologic heterogeneity is suggested by epidemiologic variations that have been observed by subsite and cell type. Among the environmental factors associated with STS are external radiation therapy, Thorotrast, arsenical pesticides and medications, phenoxyherbicides, dioxin, vinyl chloride, immunosuppressive drugs, alkylating agents, androgen-anabolic steroids, human immunodeficiency virus, and human herpes virus type 8. In addition, STS occurs excessively among persons with certain heritable states including retinoblastoma, Li-Fraumeni syndrome, Gardner's syndrome, Werner's syndrome, nevoid basal cell carcinoma syndrome, neurofibromatosis type 1, and some immunodeficiency syndromes. These risk factors account for a minority of STS cases but provide leads for further epidemiologic and interdisciplinary studies into the genetic and environmental determinants of various forms of STS.
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PMID:The epidemiology of soft tissue sarcoma. 934 16

Most of the genes involved in the pathogenesis of the DNA replication and repair syndromes have now been cloned, and our understanding of the basis for the pleiotropic phenotype associated with many of these syndromes has rapidly and dramatically expanded. The elucidation of the specific interactions between proteins that comprise the transcription factor complex TFIIH raises the possibility that nucleotide excision repair, RNA polymerase II transcription, and cell cycle control are connected. Defects in the XPB, XPD, and XPG genes can result in three different syndromes, xeroderma pigmentosum, Cockayne syndrome, or trichothiodystrophy, depending on the specific mutation involved. The recent cloning of the genes involved in Bloom syndrome (BLM) and Werner syndrome (WRN) show that both are DNA and RNA helicases with homology to each other and to other DExH box helicases, yet the mechanism by which defects in these genes cause such different phenotypes is not yet understood. The ataxia-telangiectasia gene (ATM) is involved in a variety of signal transduction pathways that regulate the cellular response to normal proliferative stimuli as well as the response to DNA damage, and the disruption of these signal transduction pathways provides an explanation for ataxia-telangiectasia characteristics such as ionizing radiation sensitivity, immunodeficiency, and infertility. Although the first Fanconi anemia gene (FAC) was cloned over 5 years ago, and a second Fanconi anemia gene (FAA) was cloned in 1996, the biochemical function of Fanconi anemia proteins largely remains a mystery. The recent construction of mutant mouse strains for several of these diseases should help unlock the difficult puzzle of the pathogenesis of these syndromes.
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PMID:Disorders of DNA replication and repair. 942 94

Two new human DNA helicase genes, RecQ4 and RecQ5, that belong to the RecQ helicase family were cloned and characterized. The addition of these genes increases the total to five helicase genes in the human RecQ family, which includes helicases involved in Bloom and Werner syndromes, the genetic diseases manifesting the distinctive but overlapping clinical phenotypes of immunodeficiency, premature aging, and an enhanced risk of cancer. The RecQ4 helicase is as large as the Bloom (BLM) and Werner (WRN) helicases, and its gene expression profile is organ-specific, resembling that of BLM helicase. In contrast, the RecQ5 helicase has a low molecular weight, similar to the human progenitor RecQ1 helicase, and is expressed in all the organs examined. All five human helicase genes are expressed in cultured K562 leukemia and fibroblast cells. Synchronized K562 cell cultures showed that the genes RecQ4 and BLM, and RecQ1 and WRN, seem to be upregulated at the G1/S and G2/M phases, respectively, of the cell cycle. The biological significance of multiple species of human RecQ helicases, which are apparently nonessential for life but may be related to distinct diseases, is discussed in light of the fact that unicellular organisms, like Escherichia coli and yeast, contain only one species of helicase of this particular family.
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PMID:Cloning of two new human helicase genes of the RecQ family: biological significance of multiple species in higher eukaryotes. 987 47

Bloom's syndrome (BS) is a rare autosomal recessive disorder characterized by stunted growth, sun-sensitive erythema and immunodeficiency. Chromosomal abnormalities are often observed. Patients with BS are highly predisposed to cancers. The causative gene for BS has been identified as BLM. The former encodes a protein, which is a homologue of the RecQ DNA helicase family, a family which includes helicases such as Esherichia coli RecQ, yeast Sgs1, and human WRN. WRN is encoded by the gene that when mutated causes Werner's syndrome. The function of BLM in DNA replication and repair has not yet been determined, however. To understand the function of BLM in haematopoietic cells and the cause of immunodeficiency in BS, expression of the BLM gene in various human tissues and haematopoietic cell lines was analysed and the involvement of BLM in immunoglobulin rearrangement examined. In contrast to WRN, BLM was expressed strongly in the testis and thymus. B, T, myelomonocytic and megakaryocytic cell lines also expressed BLM. All of the examined sequences at the junction of the variable (V), diversity (D) and joining (J) regions of the immunoglobulin heavy-chain genes were in-frame, and N-region insertions were also present. The frequency of abnormal rearrangements of the T cell receptor was slightly elevated in the peripheral T cells of patients with BS compared with healthy individuals, whereas a higher frequency of abnormal rearrangements was observed in the cells of patients with ataxia-telangiectasia (A-T). In DND39 cell lines, the induction of sterile transcription, which is required for class switching of immunoglobulin heavy-chain constant genes, was correlated with the induction of the BLM gene. Taking into consideration all these results, BLM may not be directly involved in VDJ recombination, but is apparently involved in the maintenance of the stability of DNA.
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PMID:Expression of the BLM gene in human haematopoietic cells. 1054 Jan 92

Bloom's syndrome (BS) is an autosomal recessive disorder associated with dwarfism, immunodeficiency, reduced fertility, and elevated levels of many types of cancer. BS cells show marked genomic instability; in particular, hyperrecombination between sister chromatids and homologous chromosomes. This instability is thought to result from defective processing of DNA replication intermediates. The gene mutated in BS, BLM, encodes a member of the RecQ family of DExH box DNA helicases, which also includes the Werner's syndrome gene product. We have investigated the mechanism by which BLM suppresses hyperrecombination. Here, we show that BLM selectively binds Holliday junctions in vitro and acts on recombination intermediates containing a Holliday junction to promote ATP-dependent branch migration. We present a model in which BLM disrupts potentially recombinogenic molecules that arise at sites of stalled replication forks. Our results have implications for the role of BLM as an anti-recombinase in the suppression of tumorigenesis.
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PMID:The Bloom's syndrome gene product promotes branch migration of holliday junctions. 1082 97

Bloom syndrome (BS) is a rare genetic disorder characterized by small body size, sunsensitivity, immunodeficiency and a high predisposition to various types of cancer. BLM was identified as the causative gene for BS, and BLM protein is homologous to DNA helicase. In 1995 the causative gene for BS was identified using somatic crossover point mapping and termed BLM. BLM is a 4437 bp cDNA that encodes a 1417 amino acid peptide which is homologous to ATP-dependent DNA helicases. DNA helicases are the enzymes which catalyze the unwinding of double-stranded DNA to provide single- stranded templates for the processes of replication, repair, recombination and transcription. BLM is a member of the RecQ helicase family, consisting of human WRN, RECQL and yeast Sgs1. The BLM protein translocates into the nucleus and the distal arm of the bipartite basic residues in the C-terminus of the BLM protein is essential for targeting the nucleus. Here, we also describe relationship between the BLM gene and the cancer.
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PMID:[Bloom syndrome]. 1092 24

Werner syndrome (WS) is a recessive disorder characterized by premature senescence. Bloom syndrome (BS) is a recessive disorder characterized by short stature and immunodeficiency. A common characteristic of both syndromes is genomic instability leading to tumorigenesis. WRN and BLM genes causing WS and BS, encode proteins that are closely related to the RecQ helicase. We produced WRN-/-, BLM-/- and WRN(-/-)/BLM(-/-) mutants in the chicken B-cell line DT40. WRN-/- cells showed hypersensitivities to genotoxic agents, such as 4-nitroquinoline 1-oxide, camptothecin and methyl methanesulfonate. They also showed a threefold increase in targeted integration rate of exogenous DNAs, but not in sister chromatid exchange (SCE) frequency. BLM-/- cells showed hypersensitivities to the genotoxic agents as well as ultraviolet (UV) light, in addition to a 10-fold increase in targeted integration rate and an 11-fold increase in SCE frequency. In WRN(-/-)/BLM(-/-) cells, synergistically increased hypersensitivities to the genotoxic agents were observed whereas both SCE frequencies and targeted integration rates were partially diminished compared to the single mutants. Chromosomal aberrations were also synergistically increased in WRN(-/-)/BLM(-/-) cells when irradiated with UV light in late S to G(2) phases. These results suggest that both WRN and BLM may be involved in DNA repair in a complementary fashion.
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PMID:Werner and Bloom helicases are involved in DNA repair in a complementary fashion. 1184 Mar 41


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