Abstract
BACKGROUND: Mutations in the SERPINA1 gene can result in alpha-1 antitrypsin deficiency (AATD), which may be associated with lung or liver injury. Although the S and Z alleles account for over 95% of cases of AATD, a wide variety of rare variants have been linked to deficiency and dysfunction, while other variants are associated with normal alpha-1 antitrypsin (AAT) levels and activity. Here, we present the identification and characterization of thirteen rare SERPINA1 variants discovered during the genetic diagnosis of AATD by the Progenika diagnostic network. METHODS: The new variants were identified by sequencing the exons of SERPINA1 gene in cases with discrepancies between AAT serum levels and initial genotyping. In order to determine their pathogenic impact, the variants were expressed in a cellular model and evaluated for AAT secretion, intracellular accumulation and elastase inhibitory activity. In addition, protein structural mapping of the variants and analysis of positioning and residue/atomic contacts were performed. RESULTS: The in silico and functional in vitro analysis allowed us to classify these AAT variants as six deficient (p.Val234Glu, p.Val242_Pro243insLeu, p.Leu291Phe, p.Ala308Ser, p.Pro393Thr and p.Pro393Arg), one dysfunctional (p.Thr96Ile), three normal (p.Ser71Arg, p.Ala349Pro and p.Asp365Glu) and three null alleles (p.Gln33*, p.Gln285* and p.Leu310Phefs*14). CONCLUSIONS: Functional assays and protein structural information are useful tools in the characterization of novel variants of the SERPINA1 gene. The newly characterized mutations expand the number of SERPINA1 variants with proven pathogenic effects, facilitating the diagnoses of future cases of AATD.