31 results on '"Brantly, M L"'
Search Results
2. ENVIRONMENTAL TRIGGERS IN RECURRENT APHTHOUS STOMATITIS
- Author
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Baccaglini, L., Theriaque, D. W., Brantly, M. L., and Shuster, J. J.
- Published
- 2008
3. Alpha-1-antitrypsin aerosolised augmentation abrogates neutrophil elastase-induced expression of cathepsin B and matrix metalloprotease 2 in vivo and in vitro
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Geraghty, P, Rogan, M P, Greene, C M, Brantly, M L, O’Neill, S J, Taggart, C C, and McElvaney, N G
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- 2008
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4. Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. alpha 1-Antitrypsin Deficiency Registry Study Group.
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Turino, G M, Barker, A F, Brantly, M L, Cohen, A B, Connelly, R P, Crystal, R G, Eden, E, Schluchter, M D, and Stoller, J K
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- 1996
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5. Determinants of airflow obstruction in severe alpha-1-antitrypsin deficiency
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DeMeo, D. L, primary, Sandhaus, R. A, additional, Barker, A. F, additional, Brantly, M. L, additional, Eden, E., additional, McElvaney, N G., additional, Rennard, S., additional, Burchard, E., additional, Stocks, J. M, additional, Stoller, J. K, additional, Strange, C., additional, Turino, G. M, additional, Campbell, E. J, additional, and Silverman, E. K, additional
- Published
- 2007
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6. Prevalence of Alpha-1 Antitrypsin Deficiency in Poorly Controlled Asthma—Results from the ALA-ACRC Low-Dose Theophylline Trial
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Eden, E., primary, Holbrook, J. T., additional, Brantly, M. L., additional, Turino, G. M., additional, and Wise, R. A., additional
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- 2007
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7. 53 SHORT-TERM ATORVASTATIN THERAPY INCREASES SPECIFIC ANTIBODY PRODUCTION TO TETANUS TOXOID VACCINATION IN NORMAL HEALTHY VOLUNTEERS.
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Lee, P. Y., primary, Scumpia, P. O., additional, Byars, J. A., additional, Shuster, J. J., additional, Theriaque, D. W., additional, Segal, M. S., additional, Reeves, W. H., additional, and Brantly, M. L., additional
- Published
- 2004
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8. SHORT-TERM ATORVASTATIN THERAPY INCREASES SPECIFIC ANTIBODY PRODUCTION TO TETANUS TOXOID VACCINATION IN NORMAL HEALTHY VOLUNTEERS.
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Lee, P. Y., primary, Scumpia, P. O., additional, Byars, J. A., additional, Shuster, J. J., additional, Theriaque, D. W., additional, Segal, M. S., additional, Reeves, W. H., additional, and Brantly, M. L., additional
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- 2004
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9. American Thoracic Society/European Respiratory Society: Standards in Diagnostik und Therapie bei Patienten mit Alpha-1-Antitrypsin-Mangel.
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Stoller, J. K., Snider, G. L., Brantly, M. L., Fallat, R. J., Stockley, R. A., Turino, G. M., Konietzko, N., Dirksen, A., Eden, E., Luisetti, M., Stolk, J., and Strange, C.
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- 2005
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10. Anti-neutrophil-elastase defenses of the lower respiratory tract in alpha 1-antitrypsin deficiency directly augmented with an aerosol of alpha 1-antitrypsin.
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Hubbard, Richard C., Brantly, Mark L., Sellers, Stephanie E., Mitchell, Marc E., Crystal, Ronald G., Hubbard, R C, Brantly, M L, Sellers, S E, Mitchell, M E, and Crystal, R G
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DIAGNOSTIC use of aerosols ,ALPHA 1-antitrypsin ,AEROSOLS ,ALPHA 1-antitrypsin deficiency ,ANIMAL experimentation ,CLINICAL trials ,LUNGS ,NEUTROPHILS ,PERMEABILITY ,PROTEOLYTIC enzymes ,PULMONARY alveoli ,SHEEP ,CHEMICAL inhibitors - Abstract
Study Objective: To determine if aerosolization of purified human plasma alpha 1-antitrypsin is an effective means for increasing lower respiratory anti-neutrophil-elastase defenses in alpha 1-antitrypsin deficiency.Design: Nonrandomized, before-and-after trial with a 7-day treatment period. Companion studies in animals to determine lung epithelial permeability to alpha 1-antitrypsin.Patients: Twelve patients with homozygous Z-type alpha 1-antitrypsin deficiency and mild to moderate emphysema.Interventions: Aerosol administration of human plasma alpha 1-antitrypsin, 100 mg every 12 hours for 7 days. Single, 100-mg aerosol dose to anesthetized sheep with indwelling thoracic lymph duct catheters for direct assessment of lung permeability.Measurements and Main Results: Treatment resulted in increased alpha 1-antitrypsin levels in the lung epithelial lining fluid (0.28 +/- 0.07 microM before therapy to 5.86 +/- 1.03 microM after therapy) and increased anti-neutrophil-elastase capacity (0.78 +/- 0.38 microM before therapy to 4.16 +/- 0.95 microM after therapy). Aerosolized alpha 1-antitrypsin diffused across the respiratory epithelium and entered lung interstitial lymph (in sheep) and reached the systemic circulation (in sheep and humans). No side effects were noted.Conclusion: Short-term aerosol administration of human plasma alpha 1-antitrypsin to patients with alpha 1-antitrypsin deficiency is safe and feasible, resulting in a return to normal of anti-neutrophil-elastase defenses in the lower respiratory tract. The aerosol approach, therefore, merits serious long-term evaluation as an alternative to other parenteral forms of administering therapeutic proteins. [ABSTRACT FROM AUTHOR]- Published
- 1989
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11. Production of glycosylated physiologically "normal" human alpha 1-antitrypsin by mouse fibroblasts modified by insertion of a human alpha 1-antitrypsin cDNA using a retroviral vector.
- Author
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Garver, R I, Chytil, A, Karlsson, S, Fells, G A, Brantly, M L, Courtney, M, Kantoff, P W, Nienhuis, A W, Anderson, W F, and Crystal, R G
- Abstract
Alpha 1-Antitrypsin (alpha 1AT) deficiency is a hereditary disorder characterized by reduced serum levels of alpha 1AT, resulting in destruction of the lower respiratory tract by neutrophil elastase. As an approach to augment alpha 1AT levels in this disorder with physiologically normal human alpha 1AT, we have integrated a full-length normal human alpha 1AT cDNA into the genome of mouse fibroblasts. To accomplish this, the retroviral vector N2 was modified by inserting the simian virus 40 early promoter followed by the alpha 1AT cDNA. Southern analysis demonstrated that the intact cDNA was present in the genome of selected clones of the transfected murine fibroblasts psi 2 and infected NIH 3T3. The clones produced three mRNA transcripts (5.8, 4.8, and 2.4 kilobases) containing human alpha 1AT sequences, secreted an alpha 1AT molecule recognized by an anti-human alpha 1AT antibody, with the same molecular mass (52 kDa) as normal human alpha 1AT and that complexed with and inhibited human neutrophil elastase. The psi 2 produced alpha 1AT was glycosylated, and when infused intravenously into mice, it had a serum half-life similar to normal alpha 1AT purified from human plasma and markedly longer than that of nonglycosylated human alpha 1AT cDNA-directed yeast-produced alpha 1AT. These studies demonstrate the feasibility of using a retroviral vector to insert the normal human alpha 1AT cDNA into non-alpha 1AT-producing cells, resulting in the synthesis and secretion of physiologically "normal" human alpha 1AT.
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- 1987
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12. Identification of a second mutation in the protein-coding sequence of the Z type alpha 1-antitrypsin gene.
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Nukiwa, T, Satoh, K, Brantly, M L, Ogushi, F, Fells, G A, Courtney, M, and Crystal, R G
- Abstract
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.
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- 1986
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13. Molecular Basis of the Liver and Lung Disease Associated with the α1-Antitrypsin Deficiency Allele Mmalton
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Curiel, D T, Holmes, M D, Okayama, H, Brantly, M L, Vogelmeier, C, Travis, W D, Stier, L E, Perks, W H, and Crystal, R G
- Abstract
α1-Antitrypsin (α1AT) deficiency is characterized by reduced serum levels of α1AT and a risk for the development of emphysema and liver disease. However, whereas there is an increased risk for emphysema associated with at least 10 α1AT deficiency and null alleles, the hepatic disease is observed only in a subset of these alleles, suggesting that it is not the reduced serum levels of α1AT per se which cause the liver disease. The present study characterizes the α1AT deficiency allele Mmalton, an allele that like the common Z deficiency mutation (Glu342→Lys) is associated with both α1AT deficiency and hepatic disease. Capitalizing on the identification of the homozygous inheritance of the rare Mmaltonα1AT deficiency allele, it was demonstrated that although caused by a very different mutation, the Mmaltonallele shares with the Z allele the association of liver disease with the same type of abnormalities of α1AT biosynthesis. Cloning of the Mmaltongene and sequence analysis demonstrated that it differs from the normal α1AT M2 allele by deletion of the entire codon (TTC) for residue Phe52. Liver biopsy of the Mmaltonhomozygote revealed inflammation, mild fibrosis, and intrahepatocyte accumulation of α1AT. Evaluation of de novoα1AT biosynthesis in α1AT-synthesizing cells of this individual demonstrated normal levels of α1AT mRNA transcripts but abnormal intracellular accumulation of newly synthesized α1AT at the level of the rough endoplasmic reticulum with consequent reduced α1AT secretion. Finally, retroviral gene transfer of a normal α1AT cDNA and an α1AT cDNA with the MmaltonPhe52deletion into murine cells demonstrated that the Mmaltoncells reproduced the abnormal accumulation of newly synthesized α1AT, thus directly demonstrating that the deletion mutation is responsible for the intracellular accumulation of the newly synthesized α1AT. Thus, not only is the liver disease associated with α1AT deficiency restricted to a subset of α1AT deficiency alleles, it appears to be restricted to those alleles associated with intracellular accumulation of newly synthesized α1AT, suggesting that it is the abnormal intrahepatocyte α1AT accumulation which incites the liver injury.
- Published
- 1989
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14. Survival and FEV1 decline in individuals with severe deficiency of α1-antitrypsin
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Vreim, C. E., Wu, M., Crystal, R. G., Buist, A. S., Burrows, B., Cohen, A. B., Fallat, R. J., Gadek, J. E., Rousell, R. H., Schwartz, R. S., Turino, G. M., Schluchter, M. D., Stoller, J. K., Wiedemann, H. P., Williams, G. W., Barrett, D. M., Beck, G. J., Midcalf, V., Moore, B., Sartori, P., Sherer, S. G., Zhang, R., Petty, T. L., Tomashefski J F, Jr, Brantly, M. L., Hildesheim, J., Rundquist, B., Sandhaus, R. A., Bell, C. W., Berend, J., Begle, B., Erb, D., Seidman, J., Sherman, S., Cameron, B., Weinberger, S., Rosenberg, M., Johnston, R., Arroliga, A. C., Meeker, D. P., Mehta, A., Laskowski, D., Ryan, J., Loftin, J. P., Johnson, K., Kotch, A., Clark, T., Epstein, P. E., Del Buono, P., Sandblom, R. E., Hert, R. C., Demaine, J. B., Colar, L., Eichenhorn, M. S., Mcmahan, J. P., Breite, W. M., Webb-Johnson, D., Corbett, J., Mcmanus, D., Krowka, M. J., Zeiger, T., Prakash, U. B., Staats, T., Strange, C., Baumann, M., Marc Judson, Oser, R., Soskel, N. T., Smith, V., Killian, D. N., Demicco, W., Golden, L., Hitchcock, R., Moss, J., Chu, S. C., Mcelvaney, N. G., Barnes, P., O Neil, K., Holden, D., Meth, B. M., Ashburn, R. W., Forrester, J., Sarlin, R. F., Sen, R. S., Walsh, T. E., Jones, S., and Drake, J.
15. Heritability of lung function in severe alpha-1 antitrypsin deficiency.
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DeMeo DL, Campbell EJ, Brantly ML, Barker AF, Eden E, McElvaney NG, Rennard SI, Stocks JM, Stoller JK, Strange C, Turino G, Sandhaus RA, and Silverman EK
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- Adult, Age of Onset, Aged, Cohort Studies, Humans, Middle Aged, Pulmonary Disease, Chronic Obstructive physiopathology, Respiratory Function Tests, Smoking adverse effects, Smoking genetics, Smoking physiopathology, Spirometry, Young Adult, alpha 1-Antitrypsin Deficiency diagnosis, Pulmonary Disease, Chronic Obstructive genetics, Severity of Illness Index, alpha 1-Antitrypsin genetics, alpha 1-Antitrypsin Deficiency genetics
- Abstract
Severe alpha-1 antitrypsin (AAT) deficiency is a proven genetic risk factor for COPD, but there is marked variation in the development of COPD among AAT deficient subjects. To investigate familial aggregation of lung function in subjects with AAT deficiency, we estimated heritability for forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) in 378 AAT deficient subjects from 167 families in the AAT Genetic Modifiers Study; all subjects were verified homozygous for the Z AAT deficiency allele. Heritability was evaluated for models that included and excluded an ascertainment correction, as well as for models that excluded, included and were stratified by a cigarette smoking covariate. In models without an ascertainment correction, and in all models without a covariate for smoking, no evidence for familial aggregation of lung function was observed. In models conditioned on the index proband with covariates for smoking, post-bronchodilator FEV1/FVC demonstrated significant heritability (0.26 +/- 0.14, p = 0.03). When we limited the analysis to subjects with a smoking history, post-bronchodilator FEV1 demonstrated significant heritability (0.47 +/- 0.21, p = 0.02). Severity rate phenotypes were also assessed as potential phenotypes for genetic modifier studies. Significant heritability was found with all age-of-onset threshold models that included smoking and ascertainment adjustments. Using the t-distribution, the heritability estimates ranged from 0.43 to 0.64, depending on the age-of-onset of FEV1 decline used for the severity rate calculation. Correction for ascertainment and consideration of gene-by-smoking interactions will be crucial for the identification of genes that may modify susceptibility for COPD in families with AAT deficiency., (Copyright 2008 S. Karger AG, Basel.)
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- 2009
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16. [American Thoracic Society/European Respiratory Society Statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency].
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Stoller JK, Snider GL, Brantly ML, Fallat RJ, Stockley RA, Turino GM, Konietzko N, Dirksen A, Eden E, Fallat RJ, Luisetti M, Stolk J, and Strange C
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- Documentation standards, Humans, Lung Diseases diagnosis, Lung Diseases therapy, alpha 1-Antitrypsin Deficiency diagnosis, Evidence-Based Medicine standards, alpha 1-Antitrypsin Deficiency therapy
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- 2005
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17. Endothelial nitric oxide synthase as a potential susceptibility gene in the pathogenesis of emphysema in alpha1-antitrypsin deficiency.
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Novoradovsky A, Brantly ML, Waclawiw MA, Chaudhary PP, Ihara H, Qi L, Eissa NT, Barnes PM, Gabriele KM, Ehrmantraut ME, Rogliani P, and Moss J
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- Adult, Disease Susceptibility, Gene Frequency, Genotype, Heterozygote, Homozygote, Humans, Linkage Disequilibrium, Middle Aged, Nitric Oxide Synthase Type III, Polymorphism, Genetic, Sequence Analysis, DNA, Emphysema etiology, Nitric Oxide Synthase genetics, alpha 1-Antitrypsin Deficiency enzymology
- Abstract
A role for endothelial nitric oxide synthase (NOS3) in the susceptibility of individuals with alpha1-antitrypsin (alpha1AT) deficiency to destructive lung disease was evaluated. Six polymorphic sites were identified within the NOS3 gene (i.e., -924A/G, -788C/T, -691C/T, 774C/T, 894G/T, and 1998C/G). The genotype distribution was determined in 339 patients and 94 control individuals. Frequency of the 774T allele in severely affected individuals was 0.417 versus 0.269 in control subjects (P = 0.018), whereas the 894T allele frequency was 0.427 versus 0.280 in control subjects (P = 0.024). Patients with less severe lung disease had the 774T and 894T allele frequencies of 0.289 and 0.344, respectively, similar to frequencies in a control group (P > 0.3). No direct correlation between pulmonary function and five other NOS3 polymorphisms was observed. Thus, functional allelic variants that are in linkage disequilibrium with the 774C/T and 894G/T may be present in the specified genomic area. These data are consistent with a modulatory role for NOS3 in destructive lung disease associated with alpha1AT deficiency.
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- 1999
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18. Baseline characteristics of enrollees in the National Heart, Lung and Blood Institute Registry of alpha 1-antitrypsin deficiency. Alpha 1-Antitrypsin Deficiency Registry Study Group.
- Author
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McElvaney NG, Stoller JK, Buist AS, Prakash UB, Brantly ML, Schluchter MD, and Crystal RD
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- Adult, Bronchodilator Agents therapeutic use, Female, Forced Expiratory Volume, Humans, Logistic Models, Male, National Institutes of Health (U.S.), Phenotype, Prospective Studies, Respiratory Function Tests, United States, Registries, alpha 1-Antitrypsin Deficiency
- Abstract
Objective: alpha 1-Antitrypsin (alpha 1-AT) deficiency is a hereditary disorder characterized by a high risk for the development of emphysema at an early age. In 1988, the National Heart, Lung and Blood Institute, National Institutes of Health, initiated a registry of individuals with alpha 1-AT deficiency to help define the natural history and clinical course of this disorder. This article describes demographic and clinical characteristics of subjects enrolled in the Registry at baseline., Design: Prospective longitudinal natural history study., Setting: Thirty-seven clinical centers in the United States (36 centers) and Canada (one center)., Patients: There were 1,129 subjects 18 years of age or older with severe deficiency of alpha 1-AT, defined as having serum alpha 1-AT levels < or = 11 mumol/L confirmed by a Central Phenotyping Laboratory, or a ZZ or ZNull genotype identified by genomic DNA analysis., Results: Most enrollees were symptomatic white subjects in their fourth to sixth decade, with a ZZ phenotype, a history of having smoked cigarettes, and pulmonary function tests demonstrating a pattern consistent with emphysema. Interestingly, only a small percentage were current smokers on enrollment, suggesting that this population is amenable to smoking cessation. A subgroup of individuals in the Registry with relatively normal lung function were younger, more likely to have never smoked and more likely to have come to medical attention owing to a family history of alpha 1-AT deficiency rather than symptomatic involvement., Conclusions: These results emphasize the need for increased awareness and early detection of alpha 1-AT deficiency. In this endeavor, dissemination of the information contained in the Registry to health-care professionals and the general population, along with initiation of appropriate preventative measures before significant lung damage has occurred, could have considerable benefits for individuals with this condition.
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- 1997
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19. Metallothionein synthesis and degradation in Indian childhood cirrhosis fibroblasts.
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Hahn SH, Brantly ML, Oliver C, Adamson M, Kaler SG, and Gahl WA
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- Base Sequence, Cells, Cultured, Child, DNA, Complementary genetics, Fibroblasts metabolism, Fibroblasts pathology, Humans, Liver Cirrhosis genetics, Liver Cirrhosis pathology, Metallothionein genetics, Metallothionein metabolism, Microscopy, Electron, Molecular Sequence Data, RNA, Messenger genetics, RNA, Messenger metabolism, Liver Cirrhosis metabolism, Metallothionein biosynthesis
- Abstract
Indian childhood cirrhosis (ICC) is a fatal liver disease characterized by the accumulation of copper-sulfur aggregates. We demonstrated that cultured fibroblasts from a patient with ICC contain vesicular aggregates, fibrillar whorls, and crystalloids along with dilated rough endoplasmic reticulum filled with flocculent material. Although the copper content of the fibroblasts was normal, both basal and metal-induced metallothionein (MT) synthesis was reduced in the ICC cells. The lower MT synthesis in ICC cells was seen at copper concentrations of 100, 200, and 400 microM, zinc concentrations of 50 and 100 microM, and a cadmium concentration of 2 microM. The lower MT synthesis in ICC cells was not due to failure of the cells to take up copper because 67Cu uptake kinetics were normal in the mutant cells. MT degradation was also normal in the ICC cells. The size of human MT IIA mRNA was normal in the ICC cells, but its amount was reduced under both basal and metal-induced conditions. The MT IIA gene, which is the predominant MT gene in human beings, showed no sequence alterations in any of its exons, introns, or promoter region in the ICC cells compared with normal cells. These studies demonstrate that this case of ICC represents a genetic disease with some level of expression in cultured fibroblasts; the basic defect may involve insufficient MT mRNA and protein synthesis for the copper load present. However, it remains to be determined whether reduced MT synthesis is a primary or secondary phenomenon.
- Published
- 1994
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20. Use of a highly purified alpha 1-antitrypsin standard to establish ranges for the common normal and deficient alpha 1-antitrypsin phenotypes.
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Brantly ML, Wittes JT, Vogelmeier CF, Hubbard RC, Fells GA, and Crystal RG
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- Electrophoresis, Polyacrylamide Gel, Humans, Phenotype, Reference Values, alpha 1-Antitrypsin Deficiency, alpha 1-Antitrypsin standards
- Abstract
Diagnosis of the hereditary disorder alpha 1-antitrypsin (alpha 1AT) deficiency is critically dependent on quantification of serum levels of alpha 1AT, a 52-kDa antiprotease that serves to protect the lung from destruction by neutrophil elastase. Although the measurement of serum alpha 1AT levels is not difficult, there is no international standard for alpha 1AT, and investigators in the field recognize that widely used commercially available standards vary by as much as 50 percent. To establish accurate ranges for the common normal and deficient alpha 1AT phenotypes, the present study uses a purified alpha 1AT standard to quantify the alpha 1AT serum levels of 443 individuals with common normal and deficient alpha 1AT phenotypes, including MM, ZZ, SS, MZ, MS, and SZ. Based on the observed values, a statistical model was developed to generate predicted frequency distributions of alpha 1AT serum levels for each of these phenotypes. Based on these studies, the ranges (5th to 95th percentile) for alpha 1AT serum levels of the common phenotypes are: MM, 20 to 53 mumol/L; SS, 20 to 48 mumol/L; ZZ, 3.4 to 7.0 mumol/L; MZ, 15 to 42 mumol/L; MS, 18 to 52 mumol/L; and SZ, 10 to 23 mumol/L. This alpha 1AT standard and these ranges are being used for the National alpha 1-Antitrypsin Deficiency Registry organized under the auspices of the National Heart, Lung, and Blood Institute.
- Published
- 1991
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21. Molecular analysis of the heterogeneity among the P-family of alpha-1-antitrypsin alleles.
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Holmes MD, Brantly ML, and Crystal RG
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- Aged, Base Sequence, Female, Gene Amplification, Genotype, Heterozygote, Humans, Isoelectric Focusing, Male, Middle Aged, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Protein Biosynthesis, alpha 1-Antitrypsin Deficiency, Alleles, alpha 1-Antitrypsin genetics
- Abstract
The rare P-family of alpha 1-antitrypsin (alpha 1AT) variants is defined by the position of migration of the alpha 1AT protein on isoelectric focusing of serum (IEF) between the common M and S variants. To begin to examine the molecular heterogeneity among the P-type alleles, two unrelated subjects and their families identified by IEF to be carrying a P allele were analyzed. The first, Plowell, is a deficiency allele associated with reduced serum alpha 1AT levels, and the second, Psaint albans, is associated with normal serum levels. DNA sequence analysis of Plowell, the more anodal of the two variants on IEF analysis, showed that if differed from the normal M1(Val213) allele by a single base and amino acid substitution Asp256 GAT----Val GTT. In contrast, Psaint albans, a slightly more cathodally positioned variant on IEF analysis, differed from the coding exons of the normal M1(Val213) allele by two mutations, Asp341 GAC----Asn AAC, and a silent substitution in the same codon as the Plowell variant, Asp256 GAT----Asp GAC. Evaluation of Plowell mRNA transcripts by Northern and cytoblot analyses demonstrated they were of normal size and amount, and Plowell mRNA transcripts could be translated normally in vitro. Retroviral insertion of the Plowell cDNA into the genome of 3T3 fibroblasts demonstrated that it directed the synthesis of alpha 1AT, but at levels 24% that of the Psaint albans cDNA or the normal M1 (Val213) cDNA, with a pattern of biosynthesis consistent with the concept that the Plowell alpha 1AT deficiency state results from intracellular degradation of the newly synthesized Plowell protein.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1990
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22. Alpha 1-antitrypsin Wbethesda: molecular basis of an unusual alpha 1-antitrypsin deficiency variant.
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Holmes MD, Brantly ML, Fells GA, and Crystal RG
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- Amino Acid Sequence, Base Sequence, Emphysema genetics, Female, Humans, Male, Molecular Sequence Data, Pedigree, Phenotype, alpha 1-Antitrypsin genetics, Alleles, DNA analysis, alpha 1-Antitrypsin biosynthesis, alpha 1-Antitrypsin Deficiency
- Abstract
Molecular analysis of alpha 1-antitrypsin (alpha 1AT) Wbethesda revealed that it differs from the normal M1 (Ala213) allele by a single base mutation causing an amino acid substitution Ala336 GCT----Thr ACT. Evaluation of alpha 1AT biosynthesis directed by the Wbethesda allele showed that although Wbethesda alpha 1AT mRNA was translated normally in vitro, transfection of the Wbethesda cDNA into COS-I cells was associated with human alpha 1AT secretion of 50% that of cells transfected with a normal alpha 1AT cDNA. The pattern of alpha 1AT biosynthesis was not intracellular accumulation as observed with the common Z alpha 1AT deficiency allele, but reduced intracellular alpha 1AT, suggesting intracellular degradation of the newly synthesized Wbethesda molecule. Together these observations suggest that in heterozygous combination with a Z or Null alpha 1AT allele, the Wbethesda variant causes "alpha 1AT deficiency", thus classifying it as an alpha 1AT "at risk" allele for emphysema.
- Published
- 1990
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23. Characterization of the normal alpha 1-antitrypsin allele Vmunich: a variant associated with a unique protein isoelectric focusing pattern.
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Holmes MD, Brantly ML, Curiel DT, Weidinger S, and Crystal RG
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- Amino Acid Sequence, Base Sequence, DNA genetics, Humans, Isoelectric Focusing, Molecular Sequence Data, Polymerase Chain Reaction, alpha 1-Antitrypsin analysis, Alleles, alpha 1-Antitrypsin genetics
- Abstract
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)
- Published
- 1990
24. Clinical features and history of the destructive lung disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary symptoms.
- Author
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Brantly ML, Paul LD, Miller BH, Falk RT, Wu M, and Crystal RG
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- Adolescent, Adult, Aged, Female, Humans, Lung diagnostic imaging, Male, Middle Aged, Phenotype, Pulmonary Emphysema diagnostic imaging, Pulmonary Emphysema physiopathology, Radiography, Radionuclide Imaging, Respiratory Function Tests, Ventilation-Perfusion Ratio, alpha 1-Antitrypsin genetics, Pulmonary Emphysema etiology, alpha 1-Antitrypsin Deficiency
- Abstract
Alpha-1-antitrypsin (alpha 1AT) deficiency is a hereditary disorder characterized in adults by a high risk for the development of severe destructive lung disease at an early age. The present study was designed to draw conclusions concerning the characteristics of a referral population of 124 patients with alpha 1AT deficiency and symptomatic emphysema. Typically, the alpha 1AT level was 30 mg/dl, and the alpha 1AT phenotype was almost always PiZZ. The individuals in this population were most often male, caucasian, and ex-smokers, and they had become dyspneic between 25 and 40 yr of age. Most routine blood tests were normal. The chest radiographs and ventilation-perfusion studies typically showed abnormalities with a lower zone distribution, and about one third of the study population had evidence suggestive of pulmonary hypertension. Lung function tests were typical for emphysema; the FEV1 and DLCO were the parameters most dramatically reduced, and the annual rate of decline of those parameters was greater than that of the general population. The cumulative probability of survival of this population indicated a significantly shortened lifespan with a mean survival of 16% at 60 yr of age compared with 85% for normal persons.
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- 1988
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25. Characterization of the coding sequence of the normal M4 alpha 1-antitrypsin gene.
- Author
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Okayama H, Holmes MD, Brantly ML, and Crystal RG
- Subjects
- Alleles, Amino Acid Sequence, Base Sequence, Gene Amplification, Humans, Isoelectric Point, Molecular Sequence Data, Mutation, alpha 1-Antitrypsin genetics
- Abstract
The nucleotide sequences of the common normal "M" family of alpha 1-antitrypsin (alpha 1AT) variants are known, including M1(Val213), M1(Ala213), M2 and M3. Less common, but also migrating with the "M" family on isoelectric focusing gels, is the normal M4 allele. Being relatively rare, the M4 allele is usually found in heterozygous combination with another alpha 1AT allele making sequence characterization more difficult. To facilitate analysis of the coding exons of the alpha 1AT M4 allele, a method was developed to combine blood monocyte RNA extraction, reverse transcription of the alpha 1AT mRNA, amplification with the polymerase chain reaction and direct sequencing. This analysis demonstrated that the M4 allele differs from the M1(Val213) allele by a single nucleotide substitution G--greater than A, causing the amino acid substitution Arg101 CGT--greater than His101 CAT. This same mutation is also a part of the M2 gene suggesting that this region of the alpha 1AT gene may be one of increased mutational activity.
- Published
- 1989
- Full Text
- View/download PDF
26. The alpha 1-antitrypsin gene and its mutations. Clinical consequences and strategies for therapy.
- Author
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Crystal RG, Brantly ML, Hubbard RC, Curiel DT, States DJ, and Holmes MD
- Subjects
- Alleles, Amino Acid Sequence, Gene Expression Regulation, Genetic Variation, Humans, Mutation, Phenotype, Pulmonary Emphysema enzymology, Pulmonary Emphysema etiology, Pulmonary Emphysema therapy, alpha 1-Antitrypsin Deficiency, alpha 1-Antitrypsin genetics
- Published
- 1989
- Full Text
- View/download PDF
27. Evaluation of tamoxifen as a therapy to augment alpha-1-antitrypsin concentrations in Z homozygous alpha-1-antitrypsin-deficient subjects.
- Author
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Wewers MD, Brantly ML, Casolaro MA, and Crystal RG
- Subjects
- Adult, Drug Evaluation, Female, Humans, Male, Middle Aged, alpha 1-Antitrypsin metabolism, Homozygote, Tamoxifen therapeutic use, alpha 1-Antitrypsin Deficiency
- Abstract
Tamoxifen, an agent that binds to intracytoplasmic estrogen receptors, was evaluated as a possible means of increasing alpha-1-antitrypsin (alpha 1AT) synthesis and/or secretion and thus alpha 1AT serum levels in subjects with the homozygous form of alpha 1AT deficiency. Administration of tamoxifen (10 mg twice daily) to 30 Z homozygotes for a 30-day period was not associated with adverse reactions. However, although serum alpha 1AT levels increased significantly (p less than 0.03), the increase was minor (average pretreatment levels, 32 +/- 1 mg/dl; levels at 30 days of therapy, 35 +/- 1 mg/dl) and far below the "threshold" level of 80 mg/dl considered "protective" against an increased risk for emphysema. Thus, while the concept that increasing alpha 1AT synthesis and/or secretion is a rational goal for treating the Z homozygous form of alpha 1AT deficiency, tamoxifen will not be useful in this regard.
- Published
- 1987
- Full Text
- View/download PDF
28. Rapid, nonradioactive detection of mutations in the human genome by allele-specific amplification.
- Author
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Okayama H, Curiel DT, Brantly ML, Holmes MD, and Crystal RG
- Subjects
- Base Sequence, Codon, DNA genetics, DNA-Directed DNA Polymerase, Genetic Carrier Screening, Genetic Diseases, Inborn genetics, Homozygote, Humans, Mutation, alpha 1-Antitrypsin genetics, Alleles, Gene Amplification, Genetic Diseases, Inborn diagnosis, alpha 1-Antitrypsin Deficiency
- Abstract
A simple, rapid, nonradioactive method has been developed to facilitate the direct detection of point mutations that cause genetic disease. The method operates on the basis of the specific amplification of a target allele by the polymerase chain reaction with extension primers designed such that their 3' end is placed at the mutation site. When this base is complementary to that of the specific allele, the DNA segment is amplified; when it is not complementary, the polymerase chain reaction cannot proceed. When alpha 1-antitrypsin (alpha 1AT) deficiency was used as a model, the technique of allele-specific amplification was capable of selective detection of five different mutations that cause the alpha 1AT deficiency state, including three different naturally occurring single-base substitution mutations (alleles Z, S, and Nullbellingham), an insertion mutation (Nullmattawa), and a deletion mutation (Nullgranite falls). Double-blind evaluation of 47 samples of genomic DNA demonstrated 100% accuracy of the method. The technique of allele-specific amplification is rapid, simple, and does not require the existence of a convenient restriction endonuclease site or the use of radioactive materials, and thus should have broad applicability for the detection of known genetic diseases in a highly sensitive and specific fashion.
- Published
- 1989
29. Characterization of the gene and protein of the common alpha 1-antitrypsin normal M2 allele.
- Author
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Nukiwa T, Brantly ML, Ogushi F, Fells GA, and Crystal RG
- Subjects
- Alleles, Amino Acid Sequence, Base Sequence, Cloning, Molecular, Genes, Humans, Isoelectric Point, Molecular Sequence Data, Pancreatic Elastase metabolism, Polymorphism, Restriction Fragment Length, Protein Binding, alpha 1-Antitrypsin genetics
- Abstract
The normal M2 variant of alpha 1-antitrypsin (alpha 1AT) was cloned from a genomic DNA library of an individual homozygous for this allele. Sequencing of all coding exons of the M2 gene revealed it was identical to the common M1(Val213) gene except for two bases (M1(Val213) CGT Arg101, M2 CAT His101; M1(Val213) GAA Glu376 M2 GAC Asp376). Analysis of the sequence of the M1(Val213) and M2 genes around residue 101 revealed the M1 Arg101----M2 His101 caused a loss of the cutting site for the restriction endonuclease RsaI. Using this enzyme, as well as 19-mer oligonucleotides probes centered at residues 101 and 376, evaluation of genomic DNA from 22 M1 alleles and 14 M2 alleles revealed that residue 101 was Arg in all M1 alleles and His in all M2 alleles, while residue 376 was Glu in all M1 alleles and Asp in all M2 alleles. Despite the differences in sequence at two amino acids, the M1(Val213) and M2 proteins function similarly as assessed by quantification of the association rate constant of each for their natural substrate neutrophil elastase. In the context that there are two mutations separating the M1(Val213) and M2 alleles, it is likely that there is another alpha 1AT variant that was an intermediate in the evolution of these genes.
- Published
- 1988
30. Evaluation of the S-type of alpha-1-antitrypsin as an in vivo and in vitro inhibitor of neutrophil elastase.
- Author
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Ogushi F, Hubbard RC, Fells GA, Casolaro MA, Curiel DT, Brantly ML, and Crystal RG
- Subjects
- Adult, Dose-Response Relationship, Drug, Epithelium analysis, Epithelium metabolism, Female, Haplotypes, Homozygote, Humans, Lung analysis, Lung metabolism, Male, Oxidation-Reduction, Phenotype, Pulmonary Emphysema etiology, Pulmonary Emphysema genetics, Pulmonary Emphysema metabolism, Risk Factors, Time Factors, alpha 1-Antitrypsin analysis, alpha 1-Antitrypsin genetics, alpha 1-Antitrypsin Deficiency, Neutrophils enzymology, Pancreatic Elastase antagonists & inhibitors, alpha 1-Antitrypsin pharmacology
- Abstract
S-type alpha 1-antitrypsin (alpha 1AT) is a deficiency haplotype that differs from the common normal M1 (val213) alpha 1AT haplotype by a single amino acid (glu264 to val264). To evaluate the adequacy of the antineutrophil elastase protection associated with the S homozygous state, alpha 1AT plasma and lung epithelial lining fluid (ELF) levels and antineutrophil elastase function were analyzed in 9 PISS subjects. The plasma alpha 1AT levels of SS subjects were intermediate between that of M1M1 and ZZ subjects (p less than 0.001, all comparisons) and the plasma neutrophil elastase inhibitory capacity paralleled the differences in alpha 1AT concentration (p less than 0.001, all comparisons). The association rate constant for neutrophil elastase of the purified S protein was less than that of the normal molecule (S-type, 7.1 +/- 0.1 X 10(6) M-1 s-1; M1-type, 9.6 +/- 0.2 X 10(6) M-1 s-1; p less than 0.001), but much greater than that for the Z molecule (p less than 0.001). Exposure of the purified S protein to increasing oxidant burdens resulted in a dose-dependent reduction in the ability of the molecule to inhibit neutrophil elastase in a fashion parallel to that of the M1 and Z proteins. Quantification of ELF alpha 1AT levels and antineutrophil elastase capacity demonstrated that the SS ELF parameters were, as in plasma, intermediate between M1 homozygotes and Z homozygotes. Using the association rate constant together with the quantification of ELF alpha 1AT levels, the "in vivo lung inhibition time" was estimated, yielding an assessment of the relative antineutrophil elastase screen of the PISS lower respiratory tract.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1988
- Full Text
- View/download PDF
31. Molecular basis of the liver and lung disease associated with the alpha 1-antitrypsin deficiency allele Mmalton.
- Author
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Curiel DT, Holmes MD, Okayama H, Brantly ML, Vogelmeier C, Travis WD, Stier LE, Perks WH, and Crystal RG
- Subjects
- Amino Acid Sequence, Base Sequence, Cloning, Molecular, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Neutrophils enzymology, Pancreatic Elastase antagonists & inhibitors, Pancreatic Elastase blood, Pedigree, Plasmids, RNA, Messenger genetics, Risk Factors, Smoking adverse effects, Transcription, Genetic, alpha 1-Antitrypsin genetics, alpha 1-Antitrypsin physiology, Alleles, Emphysema genetics, Genes, Lung Diseases genetics, alpha 1-Antitrypsin Deficiency
- Abstract
Alpha 1-Antitrypsin (alpha 1AT) deficiency is characterized by reduced serum levels of alpha 1AT and a risk for the development of emphysema and liver disease. However, whereas there is an increased risk for emphysema associated with at least 10 alpha 1AT deficiency and null alleles, the hepatic disease is observed only in a subset of these alleles, suggesting that it is not the reduced serum levels of alpha 1AT per se which cause the liver disease. The present study characterizes the alpha 1AT deficiency allele Mmalton, an allele that like the common Z deficiency mutation (Glu342----Lys) is associated with both alpha 1AT deficiency and hepatic disease. Capitalizing on the identification of the homozygous inheritance of the rare Mmalton alpha 1AT deficiency allele, it was demonstrated that although caused by a very different mutation, the Mmalton allele shares with the Z allele the association of liver disease with the same type of abnormalities of alpha 1AT biosynthesis. Cloning of the Mmalton gene and sequence analysis demonstrated that it differs from the normal alpha 1AT M2 allele by deletion of the entire codon (TTC) for residue Phe52. Liver biopsy of the Mmalton homozygote revealed inflammation, mild fibrosis, and intrahepatocyte accumulation of alpha 1AT. Evaluation of de novo alpha 1AT biosynthesis in alpha 1AT-synthesizing cells of this individual demonstrated normal levels of alpha 1AT mRNA transcripts but abnormal intracellular accumulation of newly synthesized alpha 1AT at the level of the rough endoplasmic reticulum with consequent reduced alpha 1AT secretion. Finally, retroviral gene transfer of a normal alpha 1AT cDNA and an alpha 1AT cDNA with the Mmalton Phe52 deletion into murine cells demonstrated that the Mmalton cells reproduced the abnormal accumulation of newly synthesized alpha 1AT, thus directly demonstrating that the deletion mutation is responsible for the intracellular accumulation of the newly synthesized alpha 1AT. Thus, not only is the liver disease associated with alpha 1AT deficiency restricted to a subset of alpha 1AT deficiency alleles, it appears to be restricted to those alleles associated with intracellular accumulation of newly synthesized alpha 1AT, suggesting that it is the abnormal intrahepatocyte alpha 1AT accumulation which incites the liver injury.
- Published
- 1989
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