Characterization of a novel SERPINA1 variant carrying two missense mutations: molecular mechanisms and functional impact

Alpha 1-Antitrypsin Deficiency (AATD) is a rare genetic disorder caused by mutations in the SERPINA1 gene, which encodes the Alpha 1-Antitrypsin (AAT) protein. Individuals carrying pathogenic SERPINA1 variants are predisposed to lung and liver damage. The most common AATD-associated SERPINA1 alleles are the S and Z alleles, though additional variants have been identified. This study describes the discovery of a new SERPINA1 variant detected in two unrelated families from two cities in southeastern France. This variant, named PiZ marseille , results from in cis combination of the PiZ allele and a rare variant known as PiZ bristol . PiZ marseille has been associated with early-onset liver disease in childhood. To further investigate this new variant, we performed its molecular and functional characterization, revealing that PiZ marseille shares the pathogenic properties of both the PiZ and PiZ bristol variants. These properties include its retention in the endoplasmic reticulum as aggregates and its degradation through the autophagy and proteasome pathways. Additionally, we conducted proteomic profiling to explore the association of this mutant with liver disease. Our analysis revealed that the neutrophil degranulation pathway is particularly deregulated in PiZ marseille liver samples. Furthermore, when compared to other AAT genotypes, the proteomic profile of PiZ marseille most closely resembles that of the PiZ variant, rather than other SERPINA1 variants.