Five rare genetic variants of the SERPINA1 gene, including 4 previously unknown mutations, might be associated with the development of alpha-1 antitrypsin deficiency (AATD), according to a new study published in Respiratory Research.

For the purpose of this study, the researchers recruited 6 patients with moderate to severe AATD from the outpatient clinic of the respiratory department of Vall d’Hebron University Hospital in Barcelona, Spain. All participants presented with discrepancies between alpha-1 antitrypsin (AAT) concentration and phenotype pattern or allele-specific genotype.

The study authors collected clinical data and performed genotyping and phenotyping assays, structural mapping, and conformational characterization through molecular dynamic simulations.

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The results identified 5 AAT missense mutations: Gly95Alafs*18 in patient 1, Val210Glu in patients 2 and 3, Asn247Ser in patient 4, Pi*S+Asp341His in patient 5, and Pi*S+Leu383Phe+Lys394Ile in patient 6. They were localized to both the interaction surface and the hydrophobic core of the protein.

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The distribution of these genetic variations across the structure uncovered Val210Glu at the solvent-exposed s4C strand and close to the “Gate” region. Asn247Ser was positioned on the accessible surface, which is important for glycan attachment. Moreover, Asp341His and Leu383Phe were found in close proximity to the “breach” and “shutter” regions.

In addition, the molecular dynamic “analysis revealed the reshaping of local interactions around the investigated substitutions,” which have different impacts on AAT conformational flexibility, hydrophobic packing, and electronic surface properties. “The most severe structural changes were observed in the double- and triple-mutant (Pi*S+Asp341His and Pi*S+Leu383Phe+Lys394Ile) molecular models,” whose carriers presented with impaired lung function, the authors wrote.

“Rare variants might be more frequent than expected, and therefore, in discordant cases, standardized screening of the S and Z alleles should be complemented by gene sequencing and structural analysis,” Gonzalez and colleagues wrote.

“The use of conventional [molecular dynamic] simulations, albeit useful to describe the changes on local interactions produced by mutations, is limited by the time-scale and impossibility to overcome large energy barriers,” they explained. “Thus, the application of enhancing sampling methods (eg, metadynamics) should be considered for the study of the conformational dynamics of AAT in future developments.”

Aside from the main disease risk genotypes, ZZ and SZ, many other variations have emerged as a result of combining with rare deficient alleles. Research has previously detected rare AAT mutations in up to 17% of clinically researched cases.


Gonzalez A, Belmonte I, Nuñez A, et al. New variants of alpha-1-antitrypsin: structural simulations and clinical expressionRespir Res. 2022;23(1):339. doi:10.1186/s12931-022-02271-8