ArticleBMC medical genetics2019
Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency.
Article in BMC medical genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 21 citations in OpenAlex.
- Rare variants in alpha 1 antitrypsin deficiency: a systematic literature review.Orphanet journal of rare diseases · 2024Pooled it
- Evaluating Alpha-1 Antitrypsin Deficiency testing across Europe to ensure diagnostic accuracy: an EARCO multicentre project.Respiratory research · 2026Article
- Delayed Diagnosis of Alpha-1 Antitrypsin Deficiency in an Elderly Patient.Diagnostics (Basel, Switzerland) · 2026Article
- Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency.Respiratory research · 2026Article
- Susceptibility of alpha-1 antitrypsin deficiency variants to polymer-blocking therapy.JCI insight · 2025Article
- Spatial covariance reveals isothiocyanate natural products adjust redox stress to restore function in alpha-1-antitrypsin deficiency.Cell reports. Medicine · 2025Article
- Prevalence of Alpha-1 Antitrypsin Deficiency Alleles in a Lithuanian Cohort of Wheezing Small Children.Advances in respiratory medicine · 2024Article
- Review
- Protein modeling and in silico analysis to assess pathogenicity ofMolecular vision · 2023Article
- New variants of alpha-1-antitrypsin: structural simulations and clinical expression.Respiratory research · 2022Article
- Alu RNA induces NLRP3 expression through TLR7 activation in α-1-antitrypsin-deficient macrophages.JCI insight · 2022Article
- Molecular characterization ofFrontiers in pediatrics · 2022Article
- The Mechanism of Mitochondrial Injury in Alpha-1 Antitrypsin Deficiency Mediated Liver Disease.International journal of molecular sciences · 2021Article
- Clinical presentations of four patients with rare Alpha 1 Antitrypsin variants identified in a single US center.Respiratory medicine case reports · 2021Article
- Variants ofTherapeutic advances in chronic disease · 2021Review
- Leveraging Population Genomics for Individualized Correction of the Hallmarks of Alpha-1 Antitrypsin Deficiency.Chronic obstructive pulmonary diseases (Miami, Fla.) · 2020Review
- New Patient-Centric Approaches to the Management of Alpha-1 Antitrypsin Deficiency.International journal of chronic obstructive pulmonary disease · 2020Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundAlpha 1 Antitrypsin (AAT) is a key serum proteinase inhibitor encoded by SERPINA1. Sequence variants of the gene can cause Alpha 1 Antitrypsin Deficiency (AATD), a condition associated with lung and liver disease. The majority of AATD cases are caused by the 'Z' and 'S' variants - single-nucleotide variations (SNVs) that result in amino acid substitutions of E342K and E264V. However, SERPINA1 is highly polymorphic, with numerous potentially clinically relevant variants reported. Novel variants continue to be discovered, and without reports of pathogenicity, it can be difficult for clinicians to determine the best course of treatment.
methodsWe assessed the utility of next-generation sequencing (NGS) and predictive computational analysis to guide the diagnosis of patients suspected of having AATD. Blood samples on serum separator cards were submitted to the DNA
resultsSamples from 23 patients were analyzed; 21 rare/novel sequence variants were identified by NGS, including splice variants (n = 2), base pair deletions (n = 1), stop codon insertions (n = 2), and SNVs (n = 16). Computational modeling of protein structures caused by the novel SNVs showed that 8 were probably deleterious, and two were possibly deleterious. For the majority of probably/possibly deleterious SNVs (I50N, P289S, M385T, M221T, D341V, V210E, P369H, V333M and A142D), the mechanism is probably via disruption of the packed hydrophobic core of AAT. Several deleterious variants occurred in combination with more common deficiency alleles, resulting in very low AAT levels.
conclusionsNGS and computational modeling are useful tools that can facilitate earlier, more precise diagnosis, and consideration for AAT therapy in AATD.
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