Prevalence of α1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review

Serres, Frederick J. de; Blanco, Ignacio

doi:10.1177/1753465812457113

Cited by 175 publications

(155 citation statements)

References 27 publications

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“…The prevalence of AATD is variable among different geographic areas and ethnic groups, where prevalence of the PiS allele is highest for countries in Southern Europe (Iberian Peninsula) and Sub-Sahara Africa. On the other hand, maximal PiZ frequencies (2-4%) are found in the southern regions of the Scandinavian countries [2].…”

Section: Introductionmentioning

confidence: 90%

Genetics of ?1 Anti-Trypsin (AAT) Deficiency

Al-Haggar¹

2014

Gene Technology

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Section: Introductionmentioning

confidence: 90%

Genetics of ?1 Anti-Trypsin (AAT) Deficiency

Al-Haggar¹

2014

Gene Technology

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“…Low circulating levels of AAT are the result of mutations in the SERPINA1 gene (MIM 107,400) (60,61), with more than 120 naturally occurring alleles identified by migration on isoelectric focusing gels and by genotyping (30,(62)(63)(64). The different forms have been classified as normal, deficient, dysfunctional, or null variants.…”

Section: Pathogenesis Of Emphysema Associated With Aat Deficiencymentioning

confidence: 99%

“…The normal allele is the M form (65), present in more than 98% of the population. The most common deficient variants are the severe Z allele, observed with high frequency in whites in Northern European countries and North America, and the milder S form, with high prevalence in the Iberian Peninsula (30,35,63). The vast majority of cases of emphysema associated with AAT deficiency are caused by homozygous inheritance of the severe Z variant, with a single amino acid substitution of lysine for glutamic acid at position 342 (E342K) (66).…”

Section: Pathogenesis Of Emphysema Associated With Aat Deficiencymentioning

confidence: 99%

“…The vast majority of cases of emphysema associated with AAT deficiency are caused by homozygous inheritance of the severe Z variant, with a single amino acid substitution of lysine for glutamic acid at position 342 (E342K) (66). The Z mutation causes the AAT protein to polymerize in hepatocytes, preventing secretion into the blood (28,30,35,(66)(67)(68)(69)(70). The S allele, a single amino acid substitution of a glutamic acid by a valine at position 264 (E264V), results in an instable protein with reduced serum half-life (71)(72)(73)(74).…”

Section: Pathogenesis Of Emphysema Associated With Aat Deficiencymentioning

confidence: 99%

“…The consequence is the development of early-onset panacinar emphysema at ages 35 to 40 years, and a reduced lifespan of approximately 15 to 20 years (3)(4)(5)(27)(28)(29). The disorder affects 70,000 to 100,000 individuals in the United States (27,30). AAT deficiency is also associated with childhood and adult liver cirrhosis and, rarely, with hepatocellular carcinoma, panniculitis, and a variety of vasculitic and autoimmune disorders (31)(32)(33)(34)(35)(36)(37)(38).…”

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confidence: 99%

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Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease

Chiuchiolo

Crystal

2016

Annals ATS

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Alpha-1 antitrypsin (AAT) deficiency, characterized by low plasma levels of the serine protease inhibitor AAT, is associated with emphysema secondary to insufficient protection of the lung from neutrophil proteases. Although AAT augmentation therapy with purified AAT protein is efficacious, it requires weekly to monthly intravenous infusion of AAT purified from pooled human plasma, has the risk of viral contamination and allergic reactions, and is costly. As an alternative, gene therapy offers the advantage of single administration, eliminating the burden of protein infusion, and reduced risks and costs. The focus of this review is to describe the various strategies for AAT gene therapy for the pulmonary manifestations of AAT deficiency and the state of the art in bringing AAT gene therapy to the bedside.

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Real-world clinical applicability of pathogenicity predictors assessed onSERPINA1mutations in alpha-1-antitrypsin deficiency

et al. 2018

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The growth of publicly available data informing upon genetic variations, mechanisms of disease, and disease subphenotypes offers great potential for personalized medicine. Computational approaches are likely required to assess a large number of novel genetic variants. However, the integration of genetic, structural, and pathophysiological data still represents a challenge for computational predictions and their clinical use. We addressed these issues for alpha-1-antitrypsin deficiency, a disease mediated by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin. We compiled a comprehensive database of SERPINA1 coding mutations and assigned them apparent pathological relevance based upon available data. "Benign" and "pathogenic" variations were used to assess performance of 31 pathogenicity predictors. Well-performing algorithms clustered the subset of variants known to be severely pathogenic with high scores. Eight new mutations identified in the ExAC database and achieving high scores were selected for characterization in cell models and showed secretory deficiency and polymer formation, supporting the predictive power of our computational approach. The behavior of the pathogenic new variants and consistent outliers were rationalized by considering the protein structural context and residue conservation. These findings highlight the potential of computational methods to provide meaningful predictions of the pathogenic significance of novel mutations and identify areas for further investigation.

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Prevalence of α1-antitrypsin deficiency alleles PIS and PIZ worldwide and effective screening for each of the five phenotypic classes PIMS, PIMZ, PISS, PISZ, and PI*ZZ: a comprehensive review

Cited by 175 publications

References 27 publications

Genetics of ?1 Anti-Trypsin (AAT) Deficiency

Genetics of ?1 Anti-Trypsin (AAT) Deficiency

Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease

Real-world clinical applicability of pathogenicity predictors assessed onSERPINA1mutations in alpha-1-antitrypsin deficiency

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