Genomes and Genes
alpha 1 antitrypsin
Summary: Plasma glycoprotein member of the serpin superfamily which inhibits TRYPSIN; NEUTROPHIL ELASTASE; and other PROTEOLYTIC ENZYMES.
- DeMeo D, Campbell E, Barker A, Brantly M, Eden E, McElvaney N, et al. IL10 polymorphisms are associated with airflow obstruction in severe alpha1-antitrypsin deficiency. Am J Respir Cell Mol Biol. 2008;38:114-20 pubmed..Haplotype analysis of IL10 SNPs suggested the strongest association with IL10 promoter SNPs. IL10 is likely an important modifier gene for the development of COPD in individuals with severe AAT deficiency. ..
- Ferrarotti I, Scabini R, Campo I, Ottaviani S, Zorzetto M, Gorrini M, et al. Laboratory diagnosis of alpha1-antitrypsin deficiency. Transl Res. 2007;150:267-74 pubmed..We also describe the diagnostic flowchart for AATD detection that we have developed accordingly. ..
- Ezzikouri S, El Feydi A, El Kihal L, Afifi R, Benazzouz M, Hassar M, et al. Prevalence of common HFE and SERPINA1 mutations in patients with hepatocellular carcinoma in a Moroccan population. Arch Med Res. 2008;39:236-41 pubmed publisher..On the contrary, HFE C282Y and SERPINA1 mutations do not contribute to hepatocellular carcinoma development. ..
- Bakker M, Putter H, Stolk J, Shaker S, Piitulainen E, Russi E, et al. Assessment of regional progression of pulmonary emphysema with CT densitometry. Chest. 2008;134:931-937 pubmed publisher..In the PiZ group, the more emphysema is distributed basally, the more progression was found in the basal area. This finding suggests that emphysema due to AATD spreads out from affected areas. ..
- Dirksen A, Piitulainen E, Parr D, Deng C, Wencker M, Shaker S, et al. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency. Eur Respir J. 2009;33:1345-53 pubmed publisher..In patients with alpha(1)-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from alpha(1)-AT augmentation. ..
- Mallya M, Phillips R, Saldanha S, Gooptu B, Brown S, Termine D, et al. Small molecules block the polymerization of Z alpha1-antitrypsin and increase the clearance of intracellular aggregates. J Med Chem. 2007;50:5357-63 pubmed..Identifying small molecules provides a novel therapy for the treatment of liver disease associated with the Z allele of alpha1-antitrypsin. ..
- Chappell S, Hadzic N, Stockley R, Guetta Baranes T, Morgan K, Kalsheker N. A polymorphism of the alpha1-antitrypsin gene represents a risk factor for liver disease. Hepatology. 2008;47:127-32 pubmed..This is the first description of a genetic modifier of liver disease in homozygous ZZ children and has potential implications for screening and possible therapies that are currently being developed. ..
- Griese M, Latzin P, Kappler M, Weckerle K, Heinzlmaier T, Bernhardt T, et al. alpha1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur Respir J. 2007;29:240-50 pubmed..The alpha(1)-antitrypsin deposition region may play a minor role for alpha(1)-antitrypsin inhalation in cystic fibrosis patients. ..
- Prins J, van der Meijden B, Kraaijenhagen R, Wielders J. Inherited chronic obstructive pulmonary disease: new selective-sequencing workup for alpha1-antitrypsin deficiency identifies 2 previously unidentified null alleles. Clin Chem. 2008;54:101-7 pubmed..Genotyping by direct sequencing of samples from patients with alpha(1)AT concentrations < or =1.0 g/L detected these alleles and identified 2 new null alleles. ..
- Petrache I, Fijalkowska I, Medler T, Skirball J, Cruz P, Zhen L, et al. alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. Am J Pathol. 2006;169:1155-66 pubmed
- Fregonese L, Stolk J, Frants R, Veldhuisen B. Alpha-1 antitrypsin Null mutations and severity of emphysema. Respir Med. 2008;102:876-84 pubmed publisher..Early detection of carriers of this genotype would be important for preventive and therapeutic interventions. ..
- McNab G, Ahmad A, Mistry D, Stockley R. Modification of gene expression and increase in alpha1-antitrypsin (alpha1-AT) secretion after homologous recombination in alpha1-AT-deficient monocytes. Hum Gene Ther. 2007;18:1171-7 pubmed..The development of this methodology to repair the gene defect in hepatocytes should have beneficial effects on secretion, thereby protecting both the lung and liver. ..
- Churg A, Wang X, Wang R, Meixner S, Pryzdial E, Wright J. Alpha1-antitrypsin suppresses TNF-alpha and MMP-12 production by cigarette smoke-stimulated macrophages. Am J Respir Cell Mol Biol. 2007;37:144-51 pubmed
- Chughtai B, O Riordan T. Potential role of inhibitors of neutrophil elastase in treating diseases of the airway. J Aerosol Med. 2004;17:289-98 pubmed
- Persson C, Subramaniyam D, Stevens T, Janciauskiene S. Do native and polymeric alpha1-antitrypsin activate human neutrophils in vitro?. Chest. 2006;129:1683-92 pubmed
- Scott B, Egner W. Does alpha1-antitrypsin phenotype PiMZ increase the risk of fibrosis in liver disease due to hepatitis C virus infection?. Eur J Gastroenterol Hepatol. 2006;18:521-3 pubmed..87 (95% confidence interval, 0.05-14). Our results do not support the hypothesis that the presence of the PiMZ phenotype predisposes to more severe fibrosis in patients with hepatitis C. ..
- Vernooy J, Reynaert N, Wolfs T, Cloots R, Haegens A, de Vries B, et al. Rapid pulmonary expression of acute-phase reactants after local lipopolysaccharide exposure in mice is followed by an interleukin-6 mediated systemic acute-phase response. Exp Lung Res. 2005;31:855-71 pubmed..In conclusion, pulmonary LPS exposure induced rapid APR expression in lung, which precedes IL-6-mediated systemic elevation of APRs associated with hepatic APRs expression. ..
- Tsutsui Y, Liu L, Gershenson A, Wintrode P. The conformational dynamics of a metastable serpin studied by hydrogen exchange and mass spectrometry. Biochemistry. 2006;45:6561-9 pubmed..A surprising degree of flexibility is seen in beta-strand 6A, and it is speculated that this flexibility may deter the formation of edge-edge polymers. ..
- Spencer L, Humphries J, Brantly M. Antibody response to aerosolized transgenic human alpha1-antitrypsin. N Engl J Med. 2005;352:2030-1 pubmed
- Lomas D. The selective advantage of alpha1-antitrypsin deficiency. Am J Respir Crit Care Med. 2006;173:1072-7 pubmed
- Ferrarotti I, Zorzetto M, Scabini R, Mazzola P, Campo I, Luisetti M. A novel method for rapid genotypic identification of alpha 1-antitrypsin variants. Diagn Mol Pathol. 2004;13:160-3 pubmed..We found a complete agreement among our results, IEF, and genotypes obtained by standard methods. We concluded that this novel method combines efficiency, ease, swiftness, and low cost. ..
- Hersh C, Dahl M, Ly N, Berkey C, Nordestgaard B, Silverman E. Chronic obstructive pulmonary disease in alpha1-antitrypsin PI MZ heterozygotes: a meta-analysis. Thorax. 2004;59:843-9 pubmed..Future studies that adjust for smoking and include other COPD related phenotypes are required to conclusively determine the risk of COPD in PI MZ heterozygotes. ..
- Mahadeva R, Atkinson C, Li Z, Stewart S, Janciauskiene S, Kelley D, et al. Polymers of Z alpha1-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo. Am J Pathol. 2005;166:377-86 pubmed..These findings may also explain the progression of emphysema in some individuals despite alpha(1)-antitrypsin replacement therapy. ..
- Ferrarotti I, Baccheschi J, Zorzetto M, Tinelli C, Corda L, Balbi B, et al. Prevalence and phenotype of subjects carrying rare variants in the Italian registry for alpha1-antitrypsin deficiency. J Med Genet. 2005;42:282-7 pubmed
- Zorzetto M, Ferrarotti I, Campo I, Balestrino A, Nava S, Gorrini M, et al. Identification of a novel alpha1-antitrypsin null variant (Q0Cairo). Diagn Mol Pathol. 2005;14:121-4 pubmed..The proposed nomenclature of Q0cairo is from the birthplace of the father of first recognized subject. Serum levels and isoelectric focusing of AAT were consistent with the presence of the Null variant. ..
- Orru G, Faa G, Pillai S, Pilloni L, Montaldo C, Pusceddu G, et al. Rapid PCR real-time genotyping of M-Malton alpha1-antitrypsin deficiency alleles by molecular beacons. Diagn Mol Pathol. 2005;14:237-42 pubmed..This technique will be useful for research and molecular diagnostic laboratories involved in the study of alpha1-antitrypsin deficiency-related diseases. ..
- Gorrini M, Ferrarotti I, Lupi A, Bosoni T, Mazzola P, Scabini R, et al. Validation of a rapid, simple method to measure alpha1-antitrypsin in human dried blood spots. Clin Chem. 2006;52:899-901 pubmed
- McDonald K, Hong L, Trombly D, Xie Q, Jackman A. Production of human alpha-1-antitrypsin from transgenic rice cell culture in a membrane bioreactor. Biotechnol Prog. 2005;21:728-34 pubmed..Active rAAT reached levels of 100-247 mg/L (4-10% of the total extracellular protein) in the cell compartment at 5-6 days postinduction, and multiple inductions of the RAmy3D promoter were demonstrated. ..
- Chappell S, Daly L, Morgan K, Guetta Baranes T, Roca J, Rabinovich R, et al. Cryptic haplotypes of SERPINA1 confer susceptibility to chronic obstructive pulmonary disease. Hum Mutat. 2006;27:103-9 pubmed..In contrast, no haplotype associations for SERPINA3 were identified. ..
- Nita I, Hollander C, Westin U, Janciauskiene S. Prolastin, a pharmaceutical preparation of purified human alpha1-antitrypsin, blocks endotoxin-mediated cytokine release. Respir Res. 2005;6:12 pubmed
- Blanco I, de Serres F, Fernandez Bustillo E, Lara B, Miravitlles M. Estimated numbers and prevalence of PI*S and PI*Z alleles of alpha1-antitrypsin deficiency in European countries. Eur Respir J. 2006;27:77-84 pubmed..A remarkable lack in number of reliable epidemiological studies and marked differences among these European countries and regions within a given country was also found. ..
- Corral J, Aznar J, Gonzalez Conejero R, Villa P, Minano A, Vaya A, et al. Homozygous deficiency of heparin cofactor II: relevance of P17 glutamate residue in serpins, relationship with conformational diseases, and role in thrombosis. Circulation. 2004;110:1303-7 pubmed..In the family under study here, however, plasma HCII deficiency was not associated with a significant clinical phenotype. ..
- Mast S, Diekman K, Karaveg K, Davis A, Sifers R, Moremen K. Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins. Glycobiology. 2005;15:421-36 pubmed..Overexpression of EDEM2 accelerates the degradation of misfolded alpha1-antitrypsin, indicating that the protein is involved in ERAD. ..
- Hidvegi T, Schmidt B, Hale P, Perlmutter D. Accumulation of mutant alpha1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkappaB, and BAP31 but not the unfolded protein response. J Biol Chem. 2005;280:39002-15 pubmed..Accumulation of mutant alpha1ATZ does activate specific signaling pathways, including caspase-12 in mouse, caspase-4 in human, NFkappaB, and BAP31, a profile that was distinct from that activated by nonpolymerogenic alpha1AT mutants. ..
- Cabrita L, Dai W, Bottomley S. Different conformational changes within the F-helix occur during serpin folding, polymerization, and proteinase inhibition. Biochemistry. 2004;43:9834-9 pubmed
- Janciauskiene S, Larsson S, Larsson P, Virtala R, Jansson L, Stevens T. Inhibition of lipopolysaccharide-mediated human monocyte activation, in vitro, by alpha1-antitrypsin. Biochem Biophys Res Commun. 2004;321:592-600 pubmed..Thus, our data demonstrate for the first time that AAT exhibits anti-inflammatory activity in vitro that is unrelated to inhibition of serine proteases. ..
- Lu Y, Choi Y, Campbell Thompson M, Li C, Tang Q, Crawford J, et al. Therapeutic level of functional human alpha 1 antitrypsin (hAAT) secreted from murine muscle transduced by adeno-associated virus (rAAV1) vector. J Gene Med. 2006;8:730-5 pubmedb>Alpha 1 antitrypsin (AAT) is a serine proteinase inhibitor (serpin)...
- Congote L. The C-terminal 26-residue peptide of serpin A1 is an inhibitor of HIV-1. Biochem Biophys Res Commun. 2006;343:617-22 pubmed..These serpin peptides represent a novel class of antiviral agents. ..
- Li W, Savinov A, Rozanov D, Golubkov V, Hedayat H, Postnova T, et al. Matrix metalloproteinase-26 is associated with estrogen-dependent malignancies and targets alpha1-antitrypsin serpin. Cancer Res. 2004;64:8657-65 pubmed..In summary, we hypothesize that MMP-26, by cleaving and inactivating the AAT serpin, operates as a unique functional link that regulates a coordinated interplay between Ser and metalloproteinases in estrogen-dependent neoplasms. ..
- Martin S, Downey D, Bilton D, Keogan M, Edgar J, Elborn J. Safety and efficacy of recombinant alpha(1)-antitrypsin therapy in cystic fibrosis. Pediatr Pulmonol. 2006;41:177-83 pubmed..This study demonstrated that nebulized rAAT is safe and well-tolerated, but has a limited effect on NE activity and other markers of inflammation. ..
- Kamimoto T, Shoji S, Hidvegi T, Mizushima N, Umebayashi K, Perlmutter D, et al. Intracellular inclusions containing mutant alpha1-antitrypsin Z are propagated in the absence of autophagic activity. J Biol Chem. 2006;281:4467-76 pubmed
- Stoller J, Aboussouan L. alpha1-Antitrypsin deficiency . 5: intravenous augmentation therapy: current understanding. Thorax. 2004;59:708-12 pubmed..The biochemical and clinical efficacy of intravenous augmentation therapy in alpha(1)-antitrypsin deficiency is reviewed, adverse events experienced with this treatment are considered, and its cost effectiveness is discussed. ..
- Kolarich D, Weber A, Turecek P, Schwarz H, Altmann F. Comprehensive glyco-proteomic analysis of human alpha1-antitrypsin and its charge isoforms. Proteomics. 2006;6:3369-80 pubmed..Fucosylation of diantennary structures was marginal and of the core alpha1,6 type. ..
- Lu Y, Parker M, Pileggi A, Zhang B, Choi Y, Molano R, et al. Human alpha 1-antitrypsin therapy induces fatal anaphylaxis in non-obese diabetic mice. Clin Exp Immunol. 2008;154:15-21 pubmed publisher..The susceptibility of NOD mice to hypersensitivity provides a significant limitation for testing of hAAT. Development of strategies to avoid this unwanted response is required to use this promising therapeutic agent for T1D. ..
- Abdul Rahman P, Lim B, Hashim O. Expression of high-abundance proteins in sera of patients with endometrial and cervical cancers: analysis using 2-DE with silver staining and lectin detection methods. Electrophoresis. 2007;28:1989-96 pubmed..Analysis by using the champedak galactose binding lectin further highlighted an unidentified protein that may be differently glycosylated in the sera of the EACa patients that were studied. ..
- Aker J, Biddle C. AANA journal course. Update for nurse anesthetists--part 4--life in the balance: the role of serpins in disease genesis and prevention. AANA J. 2007;75:349-54 pubmed..This AANA journal course reviews 2 common examples of protease inhibitor disorders, angioedema and a form of emphysema, that are of particular anesthetic relevance. ..
- Tangsilsat D, Atamasirikul K, Treepongkaruna S, Bed S, Sumritsopak R, Kunakorn M. Fecal alpha1--antitrypsin in healthy and intestinal-disorder Thai children. J Med Assoc Thai. 2007;90:1317-22 pubmed..The RID and NPL methods showed a correlation of r = 0.87 (p < 0.01) and R2 = 0.75. Random FA1-AT assay in wet stool is a non-invasive and simple test for supporting diagnosis of protein-losing enteropathy. ..
- Kasprzyk M, Dyszkiewicz W, Zwaruń D, Szydlik S, Leśniewska K, Krzyzanowski M. [The quantitative evaluation of the serum acute phase proteins (APP) of patients undergoing a curative resection for non-small cell lung cancer (NSCLC)]. Przegl Lek. 2006;63:936-40 pubmed..This could serve as a marker of higher post-operative complication rate. ..
- Strimpakos A, Syrigos K, Saif M. Pharmacogenetics in pancreatic cancer. Highlights from the 45th ASCO annual meeting. Orlando, FL, USA. May 29-June 2, 2009. JOP. 2009;10:357-60 pubmed..The authors also present here a few other abstracts of pharmacogenomic interest which had negative findings, but believed to be of clinical importance. ..
- Sakabe S, Fujinaga K, Tsuji N, Ito N, Umino A, Taniguchi M, et al. [Marked hypoalbuminemia caused by Capillaria philippinensis]. Nihon Naika Gakkai Zasshi. 2007;96:2282-3 pubmed
- Imrie H, Fowkes F, Michon P, Tavul L, Reeder J, Day K. Low prevalence of an acute phase response in asymptomatic children from a malaria-endemic area of Papua New Guinea. Am J Trop Med Hyg. 2007;76:280-4 pubmed..002). CRP levels also increased with increasing parasitemia (P < 0.001) but remained < 3.5 microg/mL. The low levels of CRP indicate that children in the Amele modulate inflammation associated with malaria. ..
- Kaushal S, Annamali M, Blomenkamp K, RUDNICK D, Halloran D, Brunt E, et al. Rapamycin reduces intrahepatic alpha-1-antitrypsin mutant Z protein polymers and liver injury in a mouse model. Exp Biol Med (Maywood). 2010;235:700-9 pubmed publisher..Application of this finding may be therapeutic in patients with a1AT deficiency by reducing the intracellular burden of the polymerized, mutant Z protein and by reducing the progression of liver injury. ..