Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies in two Jamaican Negro families, including haematological and haemoglobin analysis, haemoglobin synthesis, and globin messenger-RNA assay, have defined two alpha-thalassaemia phenotypes which resemble the severe (alpha-thalassaemia 1) and mild (alpha-thalassaemia 2) forms of the disorder described in Orientals. Genetic analysis suggests that subjects with the alpha-thalassaemia-1 phenotype are homozygous for the alpha-thalassaemia-2 determinant. Restriction-endonuclease mapping shows that alpha-thalassaemia-2 results from the deletion of one of the linked pair of alpha-chain genes. Hence the genotypes of the alpha-thalassaemia heterozygotes and homozygotes in these families are -alpha/alpha alpha and -alpha/-alpha respectively. If these are the usual alpha-thalassaemia genotypes in Negroes, these findings explain the difference in clinical expression of the disorder between Orientals and Negroes--in particular, the absence of haemoglobin Bart's hydrops and the rarity of haemoglobin-H disease in Negroes.
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PMID:Negro alpha-thalassaemia is caused by deletion of a single alpha-globin gene. 8 8

The lysosomal enzyme, beta-hexosaminidase, is composed of two chains, alpha and beta. In Tay-Sachs disease, mutations in the gene encoding the alpha-chain produce a beta-hexosaminidase deficiency that results in the storage of its natural substrate, GM2 ganglioside. To obtain the background information for the eventual identification of the mutational errors in Tay-Sachs disease and to determine possible relationships between protein and gene structure, we have characterized the intron-exon organization of the human beta-hexosaminidase alpha-chain gene. Several overlapping clones were isolated from human genomic libraries constructed in cosmid and bacteriophage vectors. The cloned genomic DNA was analyzed by restriction endonuclease mapping, Southern blotting, and DNA sequencing. It was determined that the alpha-chain gene is approximately 35 kilobases long and is split into 14 exons. Sequences which resemble the "TATA" and "CAAT" transcriptional regulatory motifs are present at the 5' end of the gene. Differential transcription or processing of the most 3' exon of the gene results in two alpha-chain mRNAs with different 3'-untranslated regions. The first exon of the gene encodes the amino-terminal portion of the alpha-chain which is removed during the proteolytic maturation of the enzyme, raising the possibility that this segment may exist as a functional domain.
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PMID:Organization of the gene encoding the human beta-hexosaminidase alpha-chain. 295 41

Human fibrinogen cDNA probes for the alpha-, beta-, and gamma-polypeptide chains have been used to isolate the corresponding genes from human genomic libraries. There is a single copy of each gene. Restriction endonuclease analysis of isolated genomic clones and human genomic DNA indicates that the human alpha-, beta-, and gamma-fibrinogen genes are closely linked in a 50-kilobase region of a single human chromosome: the alpha-gene in the middle flanked by the beta-gene on one side and the gamma-gene on the other. The alpha- and gamma-chain genes are oriented in tandem and transcribed toward the beta-chain gene. The beta-chain gene is transcribed from the opposite DNA strand toward the gamma- and alpha-chain genes. The three genes have been localized to the distal third of the long arm of chromosome 4, bands q23-q32, by in situ hybridization with fibrinogen cDNAs and by examination of DNA from multiple rodent-human somatic cell hybrids. Alternative explanations for the present arrangement of the three fibrinogen genes involve either a three-step mechanism with inversion of the alpha/gamma-region or a two-step mechanism involving remote transposition and inversion. The second more simple mechanism has a precedent in the origin of repeated regions of the fibrinogen and immunoglobulin genes.
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PMID:Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion. 298 13

In this study, we have correlated the hematological phenotype of 56 Sardinian beta o-thalassemia heterozygotes with their alpha-globin genotype as defined by restriction endonuclease mapping. We found that the coinheritance of the deletion of one alpha-globin and, more obviously, two alpha-globin genes tend to normalize the thalassemia-like hematological phenotype commonly associated with the beta o-thalassemia carrier state. On the other hand, the association of the deletion of three alpha-globin genes caused a more severe phenotype. By globin chain synthesis analysis, those beta o-thalassemia heterozygotes with the (-alpha/alpha alpha) alpha-globin genotype had less deficiency of beta-chain synthesis than did those with the normal alpha-globin genotype (alpha alpha/alpha alpha). In heterozygotes with the (-alpha/-alpha) and in those with the (--/-alpha) alpha-globin genotype the imbalance was actually reversed with a mild or marked alpha-chain synthesis excess respectively.
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PMID:Hematological phenotype of the double heterozygous state for alpha and beta thalassemia. 620 59

The diagnosis of Hb SS/GPhiladelphia disease was made in four young Nigerians from separate families. Their Hb electrophoretic patterns on cellulose acetate membrane at alkaline pH were similar to those obtained in sickle-cell haemoglobin C (HbSC) disease, but their clinical features and haematological data were consistent with the diagnosis of homozygous sickle-cell disease. Family studies also revealed that they had inherited an additional alpha-chain mutant haemoglobin. In one of the families, fingerprints of the globin peptides and amino acid analysis confirmed that the mutant haemoglobin was Hb GPhiladelphia (alpha 2 68 Asn----Lys beta 2 A). The results of the whole blood solubility test for sickle-haemoglobin provided firm support for the diagnosis of homozygous sickle-cell disease and distinguished clearly Hb SS/GPhiladelphia disease from Hb SC disease and Hb AS from Hb AGPhiladelphia heterozygotes. Restriction endonuclease mapping of the globin genes of the propositus and some relatives of one of the families revealed also that they were carriers of the alpha-thalassaemia-2 gene (deletion-type). The globin gene-analysis data indicate also that the alpha GPhiladelphia and alpha-thalassaemia genes are linked closely in Nigerians.
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PMID:Haemoglobin GPhiladelphia and its interaction with haemoglobin S and alpha-thalassaemia in Nigerians. 648 38

The presence of hemoglobin H (beta 4), resulting from a deficiency of alpha-globin chain synthesis, was observed as an acquired characteristic in the red cells of five elderly patients with myeloproliferative disorders or preleukemia. The variability in amount of hemoglobin H and in the alpha/beta globin synthesis ratios in these patients is most likely explained by the relative proportions of normal and abnormal cell populations in the peripheral blood, since some reticulocyte fractions with balanced alpha/beta globin synthesis ratios and others with almost no detectable alpha-chain production could be obtained from these patients. In one patient, the hemoglobin H virtually disappeared despite continuing disease. The amount of cytoplasmic alpha-mRNA matched the proportion of alpha-chain synthesis and, in one patient, this was also true for nuclear RNA. However, extensive analysis of the alpha-globin gene complex by restriction endonuclease mapping revealed no detectable rearrangements of the normal gene organization in any of these patients, suggesting that transcription of each pair of alpha-globin genes on each chromosome 16 is defective. These observations have important implications for both the normal regulation of alpha-globin gene expression and the molecular basis of the underlying defect that is associated with the neoplastic transformation of these cells.
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PMID:Clinical features and molecular analysis of acquired hemoglobin H disease. 688 Nov 69

We have studied the inheritance of the alpha-chain hemoglobin variant Hb G-Philadelphia (alpha 2(68 Asn leads to Lys)Beta 2) in two African-American families. Expression of the alpha-globin loci was monitored by the percentage of Hb G in these individuals. The variant represented approximately 33% of the total adult hemoglobin in some and 50% in others. alpha-Globin gene fragments were analyzed by using restricton endonucleases that cleave outside (EcoRI), within (HindIII), and between (Bgl II) the normal duplicated alpha-globin loci (alpha alpha/alpha alpha). Individuals having 33% variant lack one functioning alpha gene (alpha G/alpha alpha); those with 50% variant lack two genes, one missing on each chromosome (alpha G/alpha). Inheritance of alpha G was therefore linked to that of a chromosome with only one functional alpha-globin gene locus. This locus is probably the result of a nonhomologous crossover. Our results also suggest equal expression of the alpha-globin loci in humans because the percentages of the variant could be explained solely on the basis of the total number of alpha genes present. The percentages of Hb G as well as other hematologic data all were consistent with the number of alpha-globin genes identified by restriction endonuclease mapping. Gene mapping yields a more precise determination of the number of alpha-globin genes than does study of globin synthesis.
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PMID:Linkage of alpha G-Philadelphia to alpha-thalassemia in African-Americans . 693 36

In humans the alpha-globin genes are duplicated and closely linked. Whereas individuals heterozygous for most alpha-chain mutations possess approximately 25% abnormal hemoglobin, heterozygotes for the alpha-chain variant Hb G Philadelphia synthesize either 33% or 50% Hb G. Both variable gene dosage and interaction with alpha-thalassemia have been proposed to explain this observation. To differentiate between these models, we have performed restriction endonuclease mapping and hematological studies on individuals with Hb G from four families. In every case the alpha G locus was carried on an EcoRI or EcoRI + BamHI fragment approximately 4 kilobases shorter than that bearing the two linked alpha A loci of hematologically normal individuals. Bgl II digestion revealed that the alpha G gene is the only alpha locus on the affected chromosome. Erythrocyte indices and alpha/beta synthesis ratios indicated that the alpha G chromosome confers alpha-thalassemia. In addition to the alpha G gene, subjects who synthesized 33% Hb G possessed two alpha A genes on the homologous chromosome and exhibited the mild form of alpha-thalassemia trait ("silent carrier"). Subjects who synthesized 50% Hb G possessed a single alpha A gene trans to the alpha G locus and displayed the more pronounced form of alpha-thalassemia trait. One subject, who synthesized 100% alpha G chains and had Hb G-Hb H disease, was found to have a single nonfunctional alpha gene trans to the alpha G gene. Thus the proportion of Hb G synthesized by heterozygotes is determined by interaction with alpha-globin gene deletions cis and trans to the alpha G locus.
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PMID:Proportion of hemoglobin G Philadelphia (alpha 268 Asn leads to Lys beta 2) in heterozygotes is determined by alpha-globin gene deletions. 693 89

Two new 5'-untranslated region (5'UTR) exons were identified in the human gene for the lymphocyte-specific endonuclease recombination activating gene-1 (RAG1) required for the somatic recombination yielding functional Ag receptors. These 5'UTR exons were used in three different splice forms by jejunal lymphocytes of the T cell lineage. RAG1 mRNA containing the previously described 5'UTR exon was not expressed in these cells. Conversely, one of the new 5'UTR exons was not expressed in thymus. The new RAG1 mRNA splice forms were all expressed in immature T cells (CD2(+)CD7(+)CD3(-)). This cell population also expressed high levels of mRNA for the pre-T alpha-chain. In situ hybridization demonstrated jejunal cells expressing the new splice forms of RAG1 mRNA, both intraepithelially and in lamina propria. Pre-T alpha-chain mRNA-expressing cells were detected at the same sites. These results strongly suggest ongoing TCR gene rearrangement in human small intestinal mucosa, yielding T cells specially adapted for this environment. This seems to be achieved by two parallel processes, extrathymic T cell development and peripheral Ag-driven TCR editing.
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PMID:Extrathymic TCR gene rearrangement in human small intestine: identification of new splice forms of recombination activating gene-1 mRNA with selective tissue expression. 1450 Jun 29

Congenital afibrinogenaemia is a rare autosomal recessive coagulation disorder. Here we describe the genetic defect in the fibrinogen A alpha-chain underlying afibrinogenaemia in a Chinese family. The proposita had a life-long bleeding tendency, both her parents and paternal grandparents had a consanguineous marriage. The blood-clotting indices of the proposita and her father were prolonged, and their functional and immunologic fibrinogen was absent. To identify the mutations of fibrinogen genes in this family, all the exons and exon-intron boundaries of the three fibrinogen genes (FGA, FGB, FGG) were amplified by polymerase chain reaction, and direct sequencing of polymerase chain reaction products was performed, then the restriction endonuclease (RsaI) analysis was used to confirm the mutation. A homozygous C --> T mutation was found at nucleotide 3108 in exon 4 of the FGA gene of the proposita and her father; it is a null mutation predicting to produce severely truncated A alpha-chains because of the presence of premature termination at the Gln 150 codon (or truncated at the 131 residues according to the mature A alpha-chain). Her mother and some other family members were heterozygous. The g.3108C --> T (Gln150 --> stop) nonsense mutation in the FGA gene is a novel genetic defect of congenital afibrinogenaemia that, to our knowledge, has not been described previously.
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PMID:A novel nonsense mutation in the FGA gene in a Chinese family with congenital afibrinogenaemia. 1579 44


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