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Identification of a second mutation in the protein-coding sequence of the Z type alpha 1-antitrypsin gene 总被引:26,自引:0,他引:26
T Nukiwa K Satoh M L Brantly F Ogushi G A Fells M Courtney R G Crystal 《The Journal of biological chemistry》1986,261(34):15989-15994
This study reports the entire nucleotide sequence of the protein coding region sequence of the alpha 1-antitrypsin (alpha 1AT) Z gene, a common form of the alpha 1AT gene associated with serum alpha 1AT deficiency. In addition to Glu342 to Lys342 mutation in exon V which has been previously identified by peptide analysis, another point mutation (GTG to GCG in exon III) in the gene sequence predicts a second amino acid substitution (Val213 to Ala213) in the Z protein. This Val213 to Ala213 mutation was confirmed to be a general finding in Z type alpha 1AT gene by evaluating genomic DNA from 40 Z haplotypes using synthetic oligonucleotide gene probes directed toward the mutated exon III sequences in the Z gene. Furthermore, the exon III Val213 to Ala213 mutation eliminates a BstEII restriction endonuclease site in the alpha 1AT Z gene, allowing rapid identification of this Val213 to Ala213 substitution at the genomic DNA level. Surprisingly, when genomic DNA samples from individuals thought to be homozygous for the M1 gene (the most common alpha 1AT normal haplotype) were evaluated with BstEII, 23% of the M1 haplotypes were BstEII site negative, thus identifying a new form of M1 (i.e. M1(Ala213], likely identical to M1 but with an isoelectric focusing "silent" amino acid substitution (Val213 to Ala213). Although the relative importance of the newly identified exon III Val213 to Ala213 mutation to the pathogenesis of the abnormalities associated with the Z gene is not known, it is likely that M1(Ala213) gene represents a common "normal" polymorphism of the alpha 1AT gene that served as an evolutionary intermediate between the M1(Val213) and Z genes. 相似文献
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D T Curiel A Chytil M Courtney R G Crystal 《The Journal of biological chemistry》1989,264(18):10477-10486
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Alpha 1-antitrypsin Null(isola di procida): an alpha 1-antitrypsin deficiency allele caused by deletion of all alpha 1-antitrypsin coding exons. 总被引:1,自引:0,他引:1
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alpha 1-Antitrypsin (alpha 1AT) deficiency, a common hereditary disorder responsible for emphysema in Caucasians of northern European descent, is caused by single base substitutions, deletions, or additions in the seven exons (IA-IC and II-V), of the 12.2-kb alpha 1AT gene located on chromosome 14 at q31-32.3. Of the five known representatives of the "null" group of alpha 1AT-deficiency alleles (alpha 1AT genes incapable of producing alpha 1AT protein detectable in serum) evaluated at the gene level, all result from mutations causing the formation of stop codons in coding exons of the alpha 1AT gene. The present study identifies an alpha 1AT allele (referred to as "Null(isola di procida")) caused by complete deletion of the alpha 1AT coding exons. The Null(isola di procida) allele was identified in an individual with heterozygous inheritance of M(procida) (an allele associated with alpha 1AT deficiency) and a null allele. Although results of karyotypic analysis were normal, quantification of the copies of alpha 1AT genes in this individual revealed that the index case had only half the normal copies of alpha 1AT genes. Cloning and mapping of the Null(isola di procida) gene demonstrated a deletion of a 17-kb fragment that included exons II-V of the alpha 1AT structural gene. As a consequence of the deletion, the normal noncoding exons (IA-IC) were followed by exons II-V of the downstream alpha 1AT-like gene. Sequence analysis of the deletion demonstrated a 7-bp repeat sequence (GAGGACA) both 5' to the deletion and at the 3' end of the deletion, a 4-bp palindromic sequence (ACAG vs. CTGT) bracketing the deletion, and a novel inserted 4-bp sequence (CCTG) at the breakpoint, suggesting that the mechanism of the deletion may have been "slipped mispairing." 相似文献
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Rare deficiency types of alpha 1-antitrypsin: electrophoretic variation and DNA haplotypes. 总被引:2,自引:1,他引:1
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A deficiency of the plasma protease inhibitor alpha 1-antitrypsin (alpha 1AT), is usually associated with the deficiency allele PI*Z. However, other alleles can also produce a deficiency. Some of these rare deficiency alleles produce a low concentration (3%-15% of normal) of alpha 1AT and include Mmalton, Mduarte, Mheerlen, and Mprocida. Null, or nonproducing, alleles are associated with trace amounts (less than 1%) of plasma alpha 1AT. We have identified, using isoelectric focusing, the deficiency alleles in 222 patients (68 children and 154 adults) with alpha 1AT deficiency. In addition to PI*Z, we found low-producing alleles PI*Mmalton and PI*Mcobalt and four null (PI*QO) alleles. On the basis of a population frequency of .0122 for PI*Z, frequencies for other deficiency alleles are 1.1 x 10(-4) for PI*Mmalton, 2.5 x 10(-5) for PI*Mcobalt (which may be the same as that for PI*Mduarte, and 1.4 x 10(-4) for all null alleles combined. Using 12 polymorphic restriction sites with seven different restriction enzymes, we have obtained DNA haplotypes for each of the rare deficiency types. All of the rare deficiency alleles can be distinguished from PI*Z by their DNA haplotype, and most can be distinguished from each other. DNA haplotypes are useful to indicate the presence of new types of null alleles, to identify genetic compounds for rare deficiency alleles, and to identify the original normal allele from which each deficiency allele is derived. 相似文献
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Characterization of the M1(Ala213) type of alpha 1-antitrypsin, a newly recognized, common "normal" alpha 1-antitrypsin haplotype 总被引:9,自引:0,他引:9
T Nukiwa M Brantly F Ogushi G Fells K Satoh L Stier M Courtney R G Crystal 《Biochemistry》1987,26(17):5259-5267
alpha 1-Antitrypsin (alpha 1AT) is a highly pleomorphic 52-kDa serum glycoprotein that functions as the major inhibitor of neutrophil elastase. Of these, the most common normal alpha 1AT haplotypes identified by isoelectric focusing (IEF) of serum are those of the M family, including M1, M2, and M3. In the course of studying the alpha 1AT type Z gene, we identified a restriction endonuclease BstEII polymorphism in the M1 gene that predicted the existence of a previously unidentified, but relatively common, haplotype of M, referred to as M1(Ala213) [Nukiwa, T., Satoh, K., Brantly, M. L., Ogushi, F., Fells, G. A., Courtney, M., & Crystal, R. G. (1986) J. Biol. Chem. 261, 15989-15994]. In this study we have cloned both alpha 1AT genes from an individual heterozygous for the M1(Ala213) and M1(Val213) haplotypes. Sequencing of the coding exons of both demonstrated that they are identical except for the Ala-Val difference at residue 213. The codominant transmission of the M1(Ala213) gene was demonstrated in a family study. Evaluation of 39 genomic samples of Caucasians with the IEF haplotype M1 demonstrated haplotype frequencies of 68% for M1(Val213) and 32% for M1(Ala213). alpha 1AT serum levels of individuals inheriting the M1(Ala213) gene in a homozygous fashion were in the same range as those for homozygous M1(Val213) as was the rate of association of the M1(Ala213) protein with neutrophil elastase.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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In-frame single codon deletion in the Mmalton deficiency allele of alpha 1-antitrypsin. 总被引:6,自引:3,他引:3
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A deficiency of the plasma protease inhibitor alpha 1-antitrypsin (alpha 1AT) is usually a consequence of the PI*Z allele. Mmalton is another deficiency allele which, like Z alpha 1AT, is associated with hepatocyte inclusions and impaired secretion. We report here the sequence of the PI Mmalton allele, which contains a 3-bp deletion coding for one of two adjacent phenylalanine residues (amino acid 51 or 52 of the mature protein). Using oligonucleotide hybridization of polymerase chain reaction-amplified DNA, we have demonstrated cosegregation of the PI Mmalton protein and the 3-bp deletion in the family in which this allele was originally described and in three other, unrelated kindreds. This deletion is found exclusively in PI Mmalton alleles and not in the normal M2 alleles from which, to judge on the basis of haplotype data, the Mmalton mutation must have been derived. In polyacrylamide isoelectric focusing (PIEF) gels, the isoelectric point of Mmalton is only slightly more cathodal than M2, a finding consistent with the loss of a single uncharged amino acid. To judge on the basis of X-ray crystallography data for the normal alpha 1AT protein, the deletion of aa 51/52 would shorten one strand of the beta sheet, B6, apparently preventing normal processing and secretion. 相似文献
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L Lin B Schmidt J Teckman D H Perlmutter 《The Journal of biological chemistry》2001,276(36):33893-33898
The classical form of alpha 1-antitrypsin (alpha 1-AT) deficiency is associated with a mutant alpha 1-ATZ molecule that polymerizes in the endoplasmic reticulum (ER) of liver cells. A subgroup of individuals homozygous for the protease inhibitor (PI) Z allele develop chronic liver injury and are predisposed to hepatocellular carcinoma. In this study we evaluated the primary structure of alpha 1-AT in a family in which three affected members had severe liver disease associated with alpha 1-AT deficiency. We discovered that one sibling was a compound heterozygote with one PI Z allele and a second allele, the PI Z + saar allele, bearing the mutation that characterizes alpha 1-ATZ as well as the mutation that characterizes alpha 1-AT Saarbrucken (alpha 1-AT saar). The mutation in PI saar introduces a premature termination codon resulting in an alpha 1-AT protein truncated for 19 amino acids at its carboxyl terminus. Studies of a second sib with severe liver disease and other living family members did not reveal the presence of the alpha 1-AT saar mutation and therefore do not substantiate a role for this mutation in the liver disease phenotype of this family. However, studies of alpha 1-AT saar and alpha 1-ATZ + saar expressed in heterologous cells show that there is prolonged intracellular retention of these mutants even though they do not have polymerogenic properties. These results therefore have important implications for further understanding the fate of mutant alpha 1-AT molecules, the mechanism of ER retention, and the pathogenesis of liver injury in alpha 1-AT deficiency. 相似文献
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S D Straus G A Fells M D Wewers M Courtney L H Tessier P Tolstoshev J P Lecocq R G Crystal 《Biochemical and biophysical research communications》1985,130(3):1177-1184
alpha 1-antitrypsin (alpha 1AT) deficiency is an inherited disorder almost always associated with the development of panacinar emphysema in the fourth to fifth decades. One source of alpha 1AT for chronic replacement therapy of such individuals is that produced by E.coli directed by a cDNA coding for the human alpha 1AT molecule. Using TG1(E.coli), an alpha 1AT molecule produced by E.coli transformed with the plasmid-expressing vector pTG922, the present study shows that recombinant DNA-directed E.coli-produced alpha 1AT is as an effective inhibitor of neutrophil elastase as alpha 1AT purified from plasma. Importantly, TG1(E.coli) inhibited human neutrophil elastase with an association rate constant of 1.3 +/- 0.4X10(7) M-1 sec-1, similar to that of normal plasma alpha 1AT (1.1 +/- 0.1, p greater than 0.2). Furthermore, when TG1(E.coli) was added to alpha 1AT-deficient plasma obtained from homozygous alpha 1AT type Z individuals, the TG1(E.coli) remained functional and augmented the anti-neutrophil elastase activity of the serum proportional to the amount of TG1(E.coli) added. These observations suggest that if sufficient amounts of recombinant DNA methodology-produced alpha 1AT molecules could be safely delivered to the alveolar structures of alpha 1AT-deficient individuals, they would function to protect the alveolar walls from elastolytic attack. 相似文献
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Sequence data of the rare deficient alpha 1-antitrypsin variant PI Zaugsburg. 总被引:1,自引:1,他引:0
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Weidinger et al. recognized a rare deficient PI-variant, named PI Zaugsburg (PI Zaug), by using isoelectric focusing with a narrow pH gradient. The serum alpha 1-antitrypsin (alpha 1AT) level determined quantitatively in an individual carrying the phenotype PI M1Zaug revealed a value of 50%-60% of the normal range. The frequency of the deficient PI*Zaug allele is still unknown. Haplotyping the Zaug-affected chromosome, we found a pattern different from the common PI*Z allele described by Cox et al. Therefore, we directly sequenced the coding exons of both genes (M1 and Zaug) after PCR amplification. Zaug sequence data analysis showed the presence of the common PI*Z allele-specific mutation (M1 Glu342 GAG to Z Lys342 AAG) surprisingly occurring in an M2 ancestral gene. This is not consistent with the heretofore common finding, by Nukiwa et al. and others, that this mutation is derived from an M1 (Ala213) background gene. No further mutations were found in the PI Zaug gene. 相似文献
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Biosynthesis, processing, and secretion of M and Z variant human alpha 1-antitrypsin 总被引:15,自引:0,他引:15
The Z genetic variant of human alpha 1-antitrypsin (alpha 1AT) is associated with decreased serum alpha 1AT levels, hepatic inclusion bodies, and an increased risk of lung and liver disease. We studied the biosynthesis, processing, and secretion of normal and Z variant alpha 1AT in cell-free translation systems, reconstituted in vitro processing systems, and in the Xenopus oocyte secretory system. Human liver mRNA was prepared from normal subjects (PiMM) and from individuals homozygous for alpha 1AT deficiency (PiZZ). Cell-free translation resulted in the synthesis of 49,000-Da preproteins with a 23-amino acid signal sequence. The genetic variants were synthesized at comparable levels and could be distinguished on the basis of charge. The majority of the amino acids in the ZZ signal peptide were identified and found to be the same as those comprising the MM signal sequence. These proteins were co-translationally processed with similar efficiency by dog pancreas microsomes, producing 52,000-Da glycoproteins which were completely translocated across the endoplasmic reticulum membrane. When the human liver RNA preparations were injected into Xenopus oocytes, both of the alpha 1AT variants were synthesized intracellularly and alpha 1AT was detected in the medium of all oocytes injected with MM RNA. However, the Z variant accumulated within the microsomal vesicles of the cell and was undetectable or present at decreased levels in the medium. We conclude that the single amino acid substitution in the Z variant of alpha 1AT does not affect its synthesis or co-translational processing but that it strongly affects its transport from the rough endoplasmic reticulum through the secretory pathway. 相似文献
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alpha1-Antitrypsin (alpha1-AT) is a highly polymorphic protein. The V allele of alpha1-AT has been shown to be associated with focal glomerulosclerosis (FGS) in Negroid and mixed race South African patients. To identify mutations and polymorphisms in the gene for the V allele of alpha1-AT in five South African patients with FGS nephrotic syndrome DNA sequence analysis and restriction fragment length polymorphisms of the coding exons were carried out. Four of the patients were heterozygous for the BstEII RFLP in exon III [M1(Val213)(Ala213)] and one patient was a M1(Ala213) homozygote. The mutation for the V allele was identified in exon II as Gly-148 (GGG)-->Arg (AGG) and in all patients was associated with a silent mutation at position 158 (AAC-->AAT). The patient who was homozygous for (Ala213) also had a silent mutation at position 256 in exon III (GAT-->GAC) which was not present in any of the other four patients. Although the V allele of alpha1-AT is not associated with severe plasma deficiency, it may be in linkage disequilibrium with other genes on chromosome 14 that predispose to FGS. Furthermore, the associated silent mutation at position 158 and the Ala213 polymorphism are of interest, as these could represent an evolutionary intermediate between the M1(Ala213) and M1(Val213) subtypes. 相似文献
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Characterization of the gene and protein of the alpha 1-antitrypsin "deficiency" allele Mprocida 总被引:7,自引:0,他引:7
H Takahashi T Nukiwa K Satoh F Ogushi M Brantly G Fells L Stier M Courtney R G Crystal 《The Journal of biological chemistry》1988,263(30):15528-15534
The "deficiency" group of alpha 1-antitrypsin (alpha 1AT) alleles is characterized by alpha 1AT genes that code for alpha 1AT present in serum but in amounts insufficient to protect the lower respiratory tract from progressive destruction by its burden of neutrophil elastase. Mprocida, a rare alpha 1AT allele associated with alpha 1AT serum levels less than 10 mg/dl (normal 150-350 mg/dl), codes for an alpha 1AT molecule that focuses on immobilized pH gradient isoelectric gels slightly cathodal to the common normal M1 (Val213) protein. On a per molecule basis, Mprocida has a mildly reduced function as an inhibitor, with an association rate constant for human neutrophil elastase of 7.0 +/- 0.1 x 10(6) M-1 s-1 (normal M1 (Val213) 9.3 +/- 0.8 x 10(6), p less than 0.01). The Mprocida molecule behaves normally in vivo with a half-life similar to normal M1 alpha 1AT molecules. Restriction endonuclease mapping demonstrates that the cloned Mprocida gene was grossly intact. Sequencing of all the exons, exon-intron junctions, and the major promoter region demonstrated Mprocida to be identical to the M1 (Val213) gene except for a single base substitution in exon II coding for amino acid 41 of the mature protein (M1 (Val213) Leu41 CTG----Mprocida Pro41 CCG). Usefully, the coding sequence of the alpha 1AT residues 40-41 is recognized by the restriction endonuclease PvuII so that using a probe corresponding to this region of exon II, the Mprocida mutation can be rapidly identified by Southern analysis. Evaluation of the crystallographic structure of alpha 1AT suggests the Leu41 to Pro41 mutation may disrupt alpha-helix A in the region of Pro21-Ser45, suggesting the possibility that the alpha 1AT Mprocida molecule is unstable and degraded intracellularly prior to secretion. 相似文献
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Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z alpha 1-antitrypsin deficiency 总被引:5,自引:0,他引:5
Lawless MW Greene CM Mulgrew A Taggart CC O'Neill SJ McElvaney NG 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(9):5722-5726
Conformational diseases are a class of disorders associated with aberrant protein accumulation in tissues and cellular compartments. Z alpha1-antitrypsin (A1AT) deficiency is a genetic disease associated with accumulation of misfolded A1AT in the endoplasmic reticulum (ER) of hepatocytes. We sought to identify intracellular events involved in the molecular pathogenesis of Z A1AT-induced liver disease using an in vitro model system of Z A1AT ER accumulation. We investigated ER stress signals induced by Z A1AT and demonstrated that both the ER overload response and the unfolded protein response were activated by mutant Z A1AT, but not wild-type M A1AT. Interestingly, activation of the unfolded protein response pathway required an additional insult, whereas NF-kappa B activation, a hallmark of the ER overload response, was constitutive. These findings have important implications for the design of future therapeutics for Z A1AT liver disease and may also impact on drug design for other conformational diseases. 相似文献
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Characterization of the normal alpha 1-antitrypsin allele Vmunich: a variant associated with a unique protein isoelectric focusing pattern. 总被引:1,自引:0,他引:1
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M D Holmes M L Brantly D T Curiel S Weidinger R G Crystal 《American journal of human genetics》1990,46(4):810-816
alpha 1-Antitrypsin (alpha 1AT), the major serum inhibitor of neutrophil elastase, is a highly polymorphic protein associated with isoelectric focusing (IEF) patterns typical for each variant. alpha 1AT Vmunich, a previously unreported normal alpha 1AT variant, has a unique IEF banding pattern in which the 7 and 8 alpha 1AT protein bands focus with the normal M-type 7 and 8 bands, despite the fact that the major fraction of the Vmunich protein focuses in the "V" region of the IEF gel. To characterize the molecular basis of this variant and its unique IEF pattern, DNA sequence analysis of the coding exons of the Vmunich alpha 1AT gene was carried out using the polymerase chain reaction. The Vmunich allele differed from the common normal M1(Val213) alpha 1AT allele by a single nucleotide substitution of cytosine for adenosine, with the resultant amino acid change Asp2 GAT----Ala GCT. Inheritance of the allele was confirmed by family analysis using allele-specific amplification with the polymerase chain reaction. The Asp2----Ala mutation explains the cathodal position of the Vmunich protein on IEF, as there is a substitution of a negatively charged amino acid by a neutral one.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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Teckman JH Perlmutter DH 《American journal of physiology. Gastrointestinal and liver physiology》2000,279(5):G961-G974
Although there is evidence for specific subcellular morphological alterations in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER), it is not clear whether these morphological changes are stereotypical or if they depend on the specific misfolded protein retained. This issue may be particularly important for mutant secretory protein alpha(1)-antitrypsin (alpha(1)AT) Z because retention of this mutant protein in the ER can cause severe target organ injury, the chronic hepatitis/hepatocellular carcinoma associated with alpha(1)AT deficiency. Here we examined the morphological changes that occur in human fibroblasts engineered for expression and ER retention of mutant alpha(1)ATZ and in human liver from three alpha(1)AT-deficient patients. In addition to marked expansion and dilatation of ER, there was an intense autophagic response. Mutant alpha(1)ATZ molecules were detected in autophagosomes by immune electron microscopy, and intracellular degradation of alpha(1)ATZ was partially reduced by chemical inhibitors of autophagy. In contrast to mutant CFTRDeltaF508, expression of mutant alpha(1)ATZ in heterologous cells did not result in the formation of aggresomes. These results show that ER retention of mutant alpha(1)ATZ is associated with a marked autophagic response and raise the possibility that autophagy represents a mechanism by which liver of alpha(1)AT-deficient patients attempts to protect itself from injury and carcinogenesis. 相似文献
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P Arnaud R M Galbraith G M Galbraith R C Allen H H Fudenberg 《American journal of human genetics》1978,30(6):653-659
A new allele of alpha1AT is described. By isoelectric focusing, the microheterogeneous pattern of the variant was similar to but more cathodal than that of Pi N. This allele has therefore been tentatively designated PiNhampton(Nham). Further examination revealed that the minor bands of Nham are indistinguishable from the major bands of Z by isoelectric focusing, and a careful family study was necessary to clearly define the proband's phenotype. Pi Nham was found in association with M1, S, and Z, but to date its possession is not apparently related to clinical disorders or reduced serum levels of alpha1AT. 相似文献
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alpha 1-Antitrypsin nullGranite Falls, a nonexpressing alpha 1-antitrypsin gene associated with a frameshift to stop mutation in a coding exon 总被引:14,自引:0,他引:14
T Nukiwa H Takahashi M Brantly M Courtney R G Crystal 《The Journal of biological chemistry》1987,262(25):11999-12004
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