Molecular basis of alpha-1-antitrypsin deficiency

Brantly, Mark; Nukiwa, Toshihiro; Crystal, Ronald G.

doi:10.1016/0002-9343(88)90154-4

Cited by 372 publications

(194 citation statements)

References 144 publications

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“…The most common variants associated with both lung and liver diseases are the Z (Glu342Lys) and S (Glu264Val) mutations (Curiel et al 1989;Lomas et al 1992). The Z allele causes the most severe plasma deficiency and occurs in [95% of individuals with AATD, whilst the S allele causes a milder plasma deficiency (Brantly et al 1988). It has been estimated that in 69 countries with 4.6 billion people, there are almost 1 million individuals who have either the SZ or ZZ phenotype (de Serres et al 2007).…”

Section: The Use Of Aat Augmentation Therapy In Treatment Of Lung Dismentioning

confidence: 99%

Alpha-1 Antitrypsin: A Potent Anti-Inflammatory and Potential Novel Therapeutic Agent

Bergin

Hurley

McElvaney

et al. 2012

Arch. Immunol. Ther. Exp.

120

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Alpha-1 antitrypsin (AAT) has long been thought of as an important anti-protease in the lung where it is known to decrease the destructive effects of major proteases such as neutrophil elastase. In recent years, the perception of this protein in this simple one dimensional capacity as an anti-protease has evolved and it is now recognised that AAT has significant anti-inflammatory properties affecting a wide range of inflammatory cells, leading to its potential therapeutic use in a number of important diseases. This present review aims to discuss the described anti-inflammatory actions of AAT in modulating key immune cell functions, delineate known signalling pathways and specifically to identify the models of disease in which AAT has been shown to be effective as a therapy.

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Section: The Use Of Aat Augmentation Therapy In Treatment Of Lung Dismentioning

confidence: 99%

Alpha-1 Antitrypsin: A Potent Anti-Inflammatory and Potential Novel Therapeutic Agent

Bergin

Hurley

McElvaney

et al. 2012

Arch. Immunol. Ther. Exp.

120

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“…an M1Ala213 background and PI*S resulted from a Glu264Val replacement on a M1Val213 ancestral allele (Brantly et al 1988;Nukiwa et al 1996).…”

Section: Susana Seixas · Oscar Garcia · M Jesus Trovoada · M Teresamentioning

confidence: 99%

“…PI has a wide spectrum of protein variants that can be distinguished by isoelectric focusing including several rare variants and six common alleles that reach polymorphic frequencies in different human populations: M1, M2, M3, M4, S and Z. Sequence characterisation of these alleles has led to the differentiation of two subtypes of M1 (M1Ala213 and M1Val213) and has shown that common M variants differ in their amino acid composition at codons 101, 213 and 376 (reviewed in Brantly et al 1988). Interspecies sequence comparisons have shown that PI molecules from non-human primates possess Ala at the position corresponding to human codon 213 suggesting that common M alleles originated according to the following pathway: M1Ala213 (Arg101-Ala213-Glu376) → M1Val213 (Arg101-Val213-Glu376) → M3 (Arg101-Val213-Asp376) → M2 (His101-Val213-Asp376).…”

Section: Introductionmentioning

confidence: 99%

Patterns of haplotype diversity within the serpin gene cluster at 14q32.1: insights into the natural history of the α1-antitrypsin polymorphism

et al. 2001

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The levels of haplotype diversity associated with different alpha1-antitrypsin (PI) alleles were assessed by the analysis of three microsatellites located within or close to corticosteroid-binding globulin (CBG), alpha1-antitrypsin [PI-(TG)n] and protein C inhibitor [PCI-(TG)n] loci in three populations with different historic backgrounds: Portugal, the Basque Country and São Tomé Príncipe (Gulf of Guinea). Unlike the more distant PCI-(TG)n repeat, allelic variation at PI-(TG)n reflected distinct phases of mutational recovery of microsatellite diversity around different founder alleles and showed a considerable differentiation between alpha1-antitrypsin protein variants. In accordance with population history, the Basque sample presented overall reduced levels of microsatellite variation. The African sample, although presenting the highest PCI-(TG)n diversity, showed a lineage-specific reduction in PI-(TG)n heterozygosity within the oldest M1Ala213 variant that could have been caused by (1) selection at a closely linked locus or (2) biases in the microsatellite mutation process leading to a stable equilibrium distribution. Age estimates of alpha1-antitrypsin variants based on microsatellite variation suggest that the Z deficiency allele appeared 107-135 generations ago and could have been spread in Neolithic times. The S mutation has an older 279- to 470-generation age, indicating that its high frequencies in Iberia did not result from a recent bottleneck and that PI*S could have originated in this region. M2 and M3 types had lower age estimates than would be expected from their wide geographical distributions, suggesting that their dispersion in Europe might have been preceded by important bottlenecks.

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“…Alpha-1-antitrypsin (a 1 -AT) is a glycoprotein of 394 amino acids (molecular weight 52,000) encoded by a single SERPINA1 (formerly known as PI) gene on the long arm of chromosome 14 (14q31-32.3); it spans 12.2 kb and is organized into four coding exons (Brantly et al 1988;Stein and Carrell 1995;Fabbretti et al 1992;Kueppers and Black 1974) and three noncoding exons (1a, 1b, and 1c). Alpha-1-AT shows considerable genetic variability, having more than 100 genetically determined variants, named PIs (protease inhibitor system) (DeMeo and Silverman 2004).…”

Section: Introductionmentioning

confidence: 99%

“…The allelic variants of this gene (PIZ 15%, PIS 60%, PIP %25, PIW 80%, and PI null 0%) frequently lead to impairment of a 1 -AT activity in serum. PIZ is most common in northern Europeans, and PIS is most common in southwestern Europeans (Brantly et al 1988;Stein and Carrell 1995;Fabbretti et al 1992;Poller et al 1990). The Z protein is due to a single amino acid substitution of 342 glutamine to lysine (Nukiwa et al 1986).…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Alpha-1-Antitrypsin Deficient Alleles M3S, MZ, and ZZ by Biochemical and Molecular Methods: A Family Study

et al. 2008

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Deficiency of alpha-1-antitrypsin (alpha(1)-AT, a major protease inhibitor controlling tissue degradation) is a genetic disorder transmitted in a codominant autosomal form. It has more than 100 genetically determined variants. This study attempted to determine the degree of association between serum alpha(1)-AT levels and phenotypes and to provide a strategy for reliable laboratory evaluation of deficiencies. The study group consisted of a 38-year-old male proband with clinical features of emphysema, his first-degree relatives, and healthy controls. Family history revealed a four-generation pedigree. Genomic DNA was isolated from peripheral blood leukocytes. Alpha-1-AT levels were determined from human serum by immunonephelometry. Phenotypes were determined by isoelectric focusing of blood samples. DNA sequences of coding exons were analyzed by the amplification DNA technique and direct sequencing. Inheritance and plasma levels of the ZZ, MM, M3S, and MZ phenotypes were confirmed by the family study. In the family members with deficiencies, plasma concentrations were 22.55% +/- 5.15 (ZZ), 84.18% +/- 5.18 (M3S), and 61.06% +/- 7.15 (MZ) of the normal MM level. We found a close association between alpha(1)-AT level and genotype. A combination of genotyping, quantification, and phenotyping is the optimal strategy for the laboratory evaluation of alpha(1)-AT deficiency.

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Molecular basis of alpha-1-antitrypsin deficiency

Cited by 372 publications

References 144 publications

Alpha-1 Antitrypsin: A Potent Anti-Inflammatory and Potential Novel Therapeutic Agent

Alpha-1 Antitrypsin: A Potent Anti-Inflammatory and Potential Novel Therapeutic Agent

Patterns of haplotype diversity within the serpin gene cluster at 14q32.1: insights into the natural history of the α1-antitrypsin polymorphism

Analysis of the Alpha-1-Antitrypsin Deficient Alleles M3S, MZ, and ZZ by Biochemical and Molecular Methods: A Family Study

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