Structural and clinical characterization of novel missense variants of SERPINA1 gene causing alpha-1 antitrypsin deficiency

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Alpha-1 antitrypsin (AAT) is a serine protease inhibitor (SERPIN). Mutations in the SERPINA1 gene may contribute to reduced intrinsic activity toward neutrophil elastase and can lead to AAT deficiency (AATD). Our objective was to perform a structural and clinical characterization of the novel AAT variants involving aminoacid (aa)substitutions Methods: Genotyping was performed when there was a discrep­ancy between AAT levels and the phenotype. AAT genotype was carried out by direct sequencing of the four exons that code the SERPINA1 in DNA isolated from whole blood. The position of the new AAT variants was indicated on the crystal structure of AAT Structure-activity. The relation of the identified mutations was evaluated through in silico modelling and molecular dynamic (MD)simulations, using X-ray crystallographic data Results: 4 novel missense variants (exon III):1) AAT=75mg/dL, Asp341Asn;2)AAT=76.3mg/dL, Val210Glu;3)AAT=98.4mg/dL, Asn247Ser;4)AAT=66.8mg/dL, Val210Asp. Investigation of the structural impact of the mutations by structural mapping and MD simulations suggest that the aa changes had varying effects on the AAT conformational stability, providing a structural explanation for a reduction of circulating AAT. Conclusions: These 4 previously unknown variants of SERPINA1 define new alleles contributing to the DAAT. In discordant cases genesequencing and structural approaches may be required

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