Ottaviani, Stefania;
Bartoli, Giulia;
Carroll, Tomás P;
Gangemi, Fabrizio;
Balderacchi, Alice M;
Barzon, Valentina;
Corino, Alessandra;
... Ferrarotti, Ilaria; + view all
(2023)
Comprehensive Clinical Diagnostic Pipelines Reveal New Variants in Alpha-1-Antitrypsin Deficiency.
American Journal of Respiratory Cell and Molecular Biology
, 69
(3)
pp. 355-366.
10.1165/rcmb.2022-0470OC.
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Abstract
Alpha-1-antitrypsin deficiency (AATD) is an under-diagnosed disorder associated with mutations in the SERPINA1 gene encoding alpha-1-antitrypsin (AAT). Severe AATD can manifest as pulmonary emphysema and progressive liver disease. Besides the most common pathogenic variants S (E264V) and Z (E342K), many rarer genetic variants of AAT have been found in patients and in the general population. Here we report a panel of new SERPINA1 variants including 4 null and 16 missense alleles identified among a cohort of individuals with suspected AATD whose phenotypic follow-up showed inconclusive or atypical results. As the pathogenic significance of the missense variants was unclear purely on the basis of clinical data, the integration of computational, biochemical and cellular studies was used to define the associated risk of disease. Established pathogenicity predictors and structural analysis identified a panel of candidate damaging mutations that were characterized by expression in mammalian cell models. Polymer formation, intracellular accumulation and secretory efficiency were evaluated experimentally. Our results identified two AAT mutants with a Z-like polymerogenic severe deficiency profile (Smilano and Mcampolongo) and three milder variants (Xsarezzo, Pdublin, Ctiberias). Overall, the experimentally determined behaviour of the variants was in agreement with the pathogenicity scores of the REVEL predictor, supporting the utility of this bioinformatic tool in the initial assessment of newly identified amino acid substitutions of AAT. Our study, in addition to describing 20 new SERPINA1 variants, provides a model for a multidisciplinary approach to classification of rare AAT variants and their clinical impact on individuals with rare AATD genotypes.
| Type: | Article |
|---|---|
| Title: | Comprehensive Clinical Diagnostic Pipelines Reveal New Variants in Alpha-1-Antitrypsin Deficiency |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1165/rcmb.2022-0470OC |
| Publisher version: | https://doi.org/10.1165/rcmb.2022-0470OC |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Serpins; serpinopathies; alpha-1-antitrypsin polymers; SERPINA1 rare variants; pathogenicity predictions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10171117 |
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