Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency
Year: 2026
Type: article
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.
Source: Respiratory Research
Authors: Nerea Matamala, Lourdes Osaba, Estrella Drobnic, Sara Gil-Martín, Antonio J. Martín-Galiano, Virginia Almadana-Pacheco, Maria Jesús Cazorla, Fabio Costa, Caroline Souza-Sokoloski, Mustafa Çörtük, Mireia Serra-Fortuny, Juan Ortiz-de Saracho, Juan Antonio Lloret-Queraltó, Nuria Rodriguez-Lázaro, Francisco Javier Michel-de la Rosa, Juan Luis Rodríguez-Hermosa, Leonardo Saldaña-Pérez, Elif Akıncı, Javier Alonso, Carlos Benítez-Buelga, Gema Gómez-Mariano, José Luis López-Campos, Beatriz Martínez-Delgado
Institutions: Instituto de Salud Carlos III, Instituto de Investigación de Enfermedades Raras, Grifols (Spain), Centre for Biomedical Network Research on Rare Diseases, Hospital Universitario Virgen Macarena, Hospital Universitario Virgen de las Nieves, Hospital de Clínicas Universidade Federal do Paraná, Universidade Federal do Paraná, Sağlık Bilimleri Üniversitesi, Yedikule Teaching Hospital, Hospital Universitari de Tortosa Verge de la Cinta, Hospital El Bierzo, Hospital de Viladecans, Consorci Sanitari Garraf, Donostiako Unibertsitate Ospitalea, Universidad Complutense de Madrid, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Hospital Universitario de Getafe, Universidad Europea de Madrid, Ankara University, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Universidad de Sevilla
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,490
Funder: Instituto de Salud Carlos III
OpenAlex ID: W7126224606