首页 | 本学科首页   官方微博 | 高级检索  
相似文献
 共查询到20条相似文献,搜索用时 861 毫秒
1.
Protein C inhibitor (plasminogen activator inhibitor-3) is a plasma glycoprotein and a member of the serine proteinase inhibitor superfamily. In the present study, the human gene for protein C inhibitor was isolated and characterized from three independent phage that contained overlapping inserts coding for the entire gene. The genomic DNA was isolated and studied by restriction mapping, polymerase chain reaction analysis, and DNA sequencing. The gene was 11.5 kilobases in length and consisted of five exons separated by four introns. In addition, 0.8 kilobases of DNA from the 5'-flanking region were sequenced. The exon-intron boundaries all observed the "GT-AG" rule. The gene for protein C inhibitor was assigned to chromosome 14 by polymerase chain reaction analysis of human/hamster hybrid cell lines. The organization of the gene for protein C inhibitor is similar to the genes coding for alpha 1-antitrypsin and alpha 1-antichymotrypsin. The genes for these two proteins are also localized on chromosome 14 suggesting a recent evolution of the genes for these three proteins from a common ancestor.  相似文献   

2.
Homozygous inheritance of the null bellingham alpha 1-antitrypsin (alpha 1AT) gene is associated with early-onset emphysema, resulting from the lack of alpha 1AT to protect the lung from neutrophil elastase. Cloning and sequencing of the null bellingham gene demonstrated that the promoter region, coding exons, and all exon-intron junctions were normal except for a single base substitution in exon III, causing the normal lys217 (AAG) to become a stop codon (TAG). Evaluation of genomic DNA of family members by using oligonucleotides directed toward this region demonstrated that the index case had inherited this mutation in a homozygous fashion. Although the consequences to the individual (i.e., emphysema) are identical to those associated with the common homozygous Z mutation, the homozygous null bellingham form of alpha 1AT deficiency has a very different genetic basis.  相似文献   

3.
J J Bao  R N Sifers  V J Kidd  F D Ledley  S L Woo 《Biochemistry》1987,26(24):7755-7759
alpha 1-Antichymotrypsin belongs to a supergene family that includes alpha 1-antitrypsin, antithrombin III, ovalbumin, and angiotensinogen. The human chromosomal alpha 1-antichymotrypsin gene has been cloned and its molecular structure established. The gene is approximately 12 kb in length and contains five exons and four introns. The locations of the introns within the alpha 1-antichymotrypsin gene are identical with those of the human alpha 1-antitrypsin and angiotensinogen genes. Other members of this supergene family contain introns located at nonhomologous positions of the genes. The homologous organization of the alpha 1-antichymotrypsin and alpha 1-antitrypsin genes corresponds with the high degree of homology between their protein sequences and suggests that these loci arose by recent gene duplication. A model is presented for the evolution of both the genomic structure and the protein sequences of the serine protease inhibitor superfamily.  相似文献   

4.
A new member of the plasma protease inhibitor gene family.   总被引:2,自引:0,他引:2       下载免费PDF全文
H Ragg 《Nucleic acids research》1986,14(2):1073-1088
A 2.1-kb cDNA clone representing a new member of the protease inhibitor family was isolated from a human liver cDNA library. The inhibitor, named human Leuserpin 2 (hLS2), comprises 480 amino acids and contains a leucine residue at its putative reactive center. HLS2 is about 25-28% homologous to three human members of the plasma protease inhibitor family: antithrombin III, alpha 1-antitrypsin and alpha 1-antichymotrypsin. A comparison with published partial amino acid sequences shows that hLS2 is closely related to the thrombin inhibitor heparin cofactor II.  相似文献   

5.
Mnichinan, a variant of alpha 1-antitrypsin (alpha 1-AT) was detected in a Japanese individual with serum alpha 1-AT deficiency (18 mg/dl), associated with aggregated alpha 1-AT molecules in the hepatocytes. Cloning and sequencing of the 10,627-bp-long region containing the Mnichinan gene and the normal M1(Val213) alpha 1-AT gene revealed all five exons of the Mnichinan gene to be identical with the M1(Val213) alpha 1-AT gene, except for two changes: a TTC trinucleotide deletion in the codon for amino acid Phe52 and a G-A substitution, by which the normal Gly148 (GGG) became Arg148 (AGG). Dot blot analysis of the polymerase chain-reaction-amplified DNA derived from the proband and other family members showed both mutations to be associated with an alpha 1-AT deficiency phenotype. Ninety-eight alpha 1-AT alleles were all negative for both changes. Comparison of the region, except for five exons between the Mnichinan and M1(Val213) genes, demonstrated one base difference in the 5' flanking region and 14 base changes in the introns. All exon-intron junctions were identical, and base changes in the 5' flanking region did not seem significant. The G-A substitution in codon 148 of the Mnichinan gene could not be responsible for the alpha 1-AT deficiency phenotype because Arg- and not Gly- was located at the corresponding position of the protein C inhibitor belonging to the serine protease inhibitor superfamily. The deletion of Phe52 may cause the newly synthesized alpha 1-AT protein to aggregate, resulting in alpha 1-AT deficiency. Comparison of the alpha 1-AT gene sequences available indicated that the C-T substitution at the CpG dinucleotide has an important role in generation of variants and nucleotide changes in the noncoding regions of the alpha 1-AT gene.  相似文献   

6.
We have cloned a new species of rat Gi alpha (Gi3 alpha) cDNA and genomic DNAs for three distinct human Gi alpha proteins (Gi1 alpha, Gi2 alpha, and Gi3 alpha). Gi3 alpha cDNA codes for a protein of 354 amino acids (Mr 40,522) whose sequence is closely related but distinct from that of the previously isolated rat Gi alpha (Gi2 alpha). By screening the human genomic libraries with the two rat Gi alpha cDNAs as probes, clones encoding human Gi1 alpha, Gi2 alpha, and Gi3 alpha were isolated. The human Gi2 alpha and Gi3 alpha genes are composed of eight coding exons and seven introns and possess a completely identical exon-intron organization. Southern blot analysis indicates that a single copy of each Gi alpha gene is present per haploid human genome.  相似文献   

7.
Forsyth S  Horvath A  Coughlin P 《Genomics》2003,81(3):336-345
The major human plasma protease inhibitors, alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, are each encoded by a single gene, whereas in the mouse they are represented by clusters of 5 and 14 genes, respectively. Although there is a high degree of overall sequence similarity within these groupings, the reactive-center loop (RCL) domain, which determines target protease specificity, is markedly divergent. The literature dealing with members of these mouse serine protease inhibitor (serpin) clusters has been complicated by inconsistent nomenclature. Furthermore, some investigators, unaware of the complexity of the family, have failed to distinguish between closely related genes when measuring expression levels or functional activity. We have reviewed the literature dealing with the mouse equivalents of human alpha(1)-antitrypsin and alpha(1)-antichymotrypsin and made use of the recently completed mouse genome sequence to propose a systematic nomenclature. We have also examined the extended mouse clade "a" serpin cluster at chromosome 12F1 and compared it with the syntenic region at human chromosome 14q32. In summarizing the literature and suggesting a standardized nomenclature, we aim to provide a logical structure on which future research may be based.  相似文献   

8.
Szalai C  Toth S  Falus A 《Gene》2000,243(1-2):161-166
The exon-intron organization and sequences of the exon-intron boundaries of the human gp130 transmembrane receptor gene have been determined using genomic DNAs as samples. The gp130 gene comprises 17 exons and 16 introns. The positions of the exon-intron boundaries show good correlation to the functional/homology regions of gp130. Exons 3-17 code for the gp130 protein, and each subdomain of the receptor is encoded by a set of exons. The coding potential of exons and the intron phasing of the human gp130 gene conform to the patterns observed previously for other cytokine receptor genes. This supports the notions that the gp130 gene evolved from the same ancestral gene that gave rise to other members of the cytokine receptor family.  相似文献   

9.
J Olsen  H Sj?str?m  O Norén 《FEBS letters》1989,251(1-2):275-281
We have isolated four lambda-phages covering the complete pig aminopeptidase N/CD13 gene. The sequence of 2.85 kbp encompasses 1.18 kbp of the 5' upstream region and 1.67 kbp of the structural gene. In the promoter region we find a TATA box and potential binding sites for CTF-1/NF-1 and AP-2. By sequence comparisons we have found three domains showing similarity to promoter regions of the genes encoding human alpha 1-antitrypsin and human intestinal alkaline phosphatase. The gene sequence includes the first three exons and two introns. It shows that a single exon encodes the cytoplasmic tail, the membrane anchor and the junctional peptide.  相似文献   

10.
11.
12.
1. Human alpha 1-antitrypsin (alpha 1 AT) has been extensively characterized and reviewed. It is the archetypal member of the superfamily of serine proteinase inhibitors, the serpins. As human alpha 1-antitrypsin exhibits a relatively high concentration in plasma and is usually the highest concentration serpin, it can be referred to as the major plasma serpin. 2. alpha 1-Antitrypsin from species other than man has been characterized for two major reasons: (1) for use in a model animal system to assist with the study of the human alpha 1 AT deficiency disease; and (2) to find polymorphism for use in gene mapping and linkage studies or for parentage analysis. 3. The diverse range of reasons for studying alpha 1AT has yielded a vast array of literature that is often not well cross-referenced. 4. The characteristic features of alpha 1AT in all species examined to date will be presented with a view to examining which features are important structurally and functionally from an evolutionary perspective. 5. In mouse, horse, rabbit and guinea pig, multigene families which appear to have arisen from alpha 1AT have been found. The functional and evolutionary implications of these paralogous genes will also be discussed.  相似文献   

13.
The three members of the serpin family, corticosteroid binding globulin, alpha1-antitrypsin, and C1 inhibitor are secreted apically from Madin-Darby canine kidney (MDCK) cells, whereas two homologous family members, antithrombin and plasminogen activator inhibitor-1, are secreted in a nonpolarized fashion. cDNAs coding for chimeras composed of complementary portions of an apically targeted serpin and a nonsorted serpin were generated, expressed in MDCK cells, and the ratio between apical and basolateral secretion was analyzed. These experiments identified an amino-terminal sequence of corticosteroid binding globulin (residues 1-19) that is sufficient to direct a chimera with antithrombin mainly to the apical side. A deletion/mutagenesis analysis showed that no individual amino acid is absolutely required for the apical targeting ability of amino acids 1-30 of corticosteroid binding globulin. The corresponding amino-terminal sequences of alpha1-antitrypsin and C1 inhibitor were also sufficient to confer apical sorting. Based on our results we suggest that the apical targeting ability is encoded in the conformation of the protein.  相似文献   

14.
The alpha 1-antitrypsin gene and its deficiency states   总被引:10,自引:0,他引:10  
alpha 1-antitrypsin, a 52 kDa antiprotease, provides the major defense to the lower respiratory tract against the ravages of neutrophil elastase, a powerful serine protease. A variety of mutations in the coding exons of the alpha 1-antitrypsin gene result in 'alpha 1-antitrypsin deficiency', leading to emphysema at an early age. A subset of mutations cause liver disease and a rare mutation is associated with a bleeding diathesis. Preventive treatment for the emphysema associated with alpha 1-antitrypsin deficiency is available in the form of intermittent infusions with alpha 1-antitrypsin, and strategies have been developed to reverse the deficiency state with gene therapy.  相似文献   

15.
16.
alpha 1-Antitrypsin (alpha 1-AT) deficiency is a hereditary disorder associated with serum alpha 1-AT levels less than 35% of normal. There are two categories of alpha 1-AT genes that cause this state: the deficient alleles, in which alpha 1-AT is present in serum but in low levels, and the null alleles, in which no alpha 1-AT in serum can be attributed to the gene. The present study defines the molecular basis for the alpha 1-AT gene nullGranite Falls, identified and cloned from genomic DNA of an individual with severe alpha 1-AT deficiency and emphysema resulting from the heterozygous inheritance of the nullGranite Falls and Z alpha 1-AT genes. Sequencing of the 5'-flanking region, all five coding exons, and all exon-intron junctions of nullGranite Falls demonstrated it was identical with the common normal M1(Ala213) alpha 1-AT gene, except for two bases: a single deletion in the codon for amino acid Tyr160 of the mature protein and a single base substitution 168 base pairs 5' to exon I. Although no role for the promoter region mutation could be assigned, the coding exon deletion [Tyr(TAC)----(TA-)] resulted in a frameshift causing a stop coding to be formed approximately 44% from the N terminus of the precursor protein. Using oligonucleotide probes to evaluate the family of the index case demonstrated the deletion----frameshift/stop mutation was inherited in an autosomal co-dominant fashion. Thus, although the molecular basis for alpha 1-AT deficiency of the alpha 1-AT null haplotype such as nullGranite Falls is very different from the molecular basis of the more common deficient haplotypes such as Z, the phenotypic consequences of the two genes are similar; i.e. severe alpha 1-AT deficiency and an association of a high risk for the development of emphysema.  相似文献   

17.
Rollini P  Fournier RE 《Genomics》1999,56(1):22-30
The genes encoding alpha1-antitrypsin (alpha1AT, gene symbol PI) and corticosteroid-binding globulin (CBG) are part of a cluster of six serine protease inhibitor (serpin) genes located on human chromosome 14q32.1. Both genes are actively transcribed in the liver and in human hepatoma cells, but they are not expressed in most other cell types. In this study we mapped DNase I-hypersensitive sites (DHSs) in an approximately 130-kb region of 14q32.1 that includes both genes. The distributions of DHSs in expressing (HepG2) vs nonexpressing (HeLa S3) cells were very different: HepG2 cells displayed 29 DHSs in this interval, but only 7 of those sites were present in HeLa cells. To determine the chromatin organization of activated or extinguished serpin alleles, we transferred human chromosome 14 into rat hepatoma cells or fibroblasts, respectively. Human alpha1AT and CBG gene expression was activated in rat hepatoma microcell hybrids containing human chromosome 14, but extinguished in rat fibroblast hybrids with the same genotype. DHS mapping in these microcell hybrids demonstrated that the chromatin structure of the entire 130-kb region was reorganized in microcell hybrids, and the distributions of DHSs in activated and extinguished alleles recapitulated those of expressing and nonexpressing cells, respectively. Thus, microcell hybrids provide a system in which reproducible changes in gene activity and long-range chromatin organization can be induced experimentally. This provides a basis for studying the effects of targeted modifications of the alpha1AT and CBG loci on the regulation of gene activity and chromatin structure.  相似文献   

18.
19.
A Lindqvist  P Rouet  J P Salier  B Akerstr?m 《Gene》1999,234(2):329-336
The 129Sv mouse gene coding for the alpha1-microglobulin/bikunin precursor has been isolated and characterized. The 11kb long gene contains ten exons, including six 5'-exons coding for alpha1-microglobulin and four 3'-exons encoding bikunin. Exon 7 also codes for the tribasic tetrapeptide RARR which connects the alpha1-microglobulin and bikunin parts. The sixth intron, which separates the alpha1-microglobulin and bikunin encoding parts, was compared in the human, mouse and a fish (plaice) gene. The size of this intron varies considerably, 6.5, 3.3 and 0.1kb in man, mouse and plaice, respectively. In all three genes, this intron contains A/T-rich regions, and retroposon elements are found in the first two genes. This indicates that this sixth intron is an unstable region and a hotspot for recombinational events, supporting the concept that the alpha1-microglobulin and bikunin parts of this gene are assembled from two ancestral genes. Finally, the nonsynonymous nucleotide substitution rate of the gene was determined by comparing coding sequences from ten vertebrate species. The results indicate that the alpha1-microglobulin part of the gene has evolved faster than the bikunin part.  相似文献   

20.
We recently cloned and sequenced alpha 1 (VIII) collagen cDNAs and demonstrated that type VIII collagen is a short-chain collagen that contains both triple helical and carboxyl-terminal non-triple helical domains similar to those of type X collagen (Yamaguchi, N., Benya, P., van der Rest, M., and Ninomiya, Y. (1989) J. Biol. Chem. 264, 16022-16029). We report here on the structural organization of the gene encoding the rabbit alpha 1 (VIII) collagen chain. The alpha 1 (VIII) gene contains four exons, whose sizes are 69, 120, 331, and 2278 base pairs. The first and second exons encode only 5'-untranslated sequences, whereas the third exon codes for a very short (3 nucleotides) stretch of 5'-untranslated sequence, the signal peptide, and almost the entire amino-terminal non-triple helical (NC2) domain (109 1/3 codons). Interestingly, the last exon encodes the rest of the translated region, including 7 2/3 codons of the NC2 domains, the complete triple helical domain (COL1, 454 amino acid residues), the entire carboxyl-terminal non-triple helical domain (NC1, 173 amino acid residues), and the 3'-untranslated region. This exon-intron structure is in stark contrast to the multi-exon structure of the fibrillar collagen (types I, II, III, V, and XI) genes, but it is remarkably similar to that of the type X collagen gene (LuValle, P., Ninomiya, Y., Rosenblum, N. D., and Olsen, B. R. (1988) J. Biol. Chem. 263, 18278-18385). The data suggest that the alpha 1 (VIII) and the alpha 1 (X) genes belong to the same subclass within the collagen family and that they arose from a common evolutionary precursor.  相似文献   

设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号