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<sub>marseille</sub>, results from in cis combination of the PiZ allele and a rare variant known as PiZ<sub>bristol</sub>. PiZ<sub>marseille</sub> 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<sub>marseille</sub> shares the pathogenic properties of both the PiZ and PiZ<sub>bristol</sub> 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<sub>marseille</sub> liver samples. Furthermore, when compared to other AAT genotypes, the proteomic profile of PiZ<sub>marseille</sub> most closely resembles that of the PiZ variant, rather than other SERPINA1 variants.

Authors

Institutions

Publication Details

Journal
Orphanet Journal of Rare Diseases
Published
2025-11-21
DOI
https://doi.org/10.1186/s13023-025-04142-z
Primary Topic
Protease and Inhibitor Mechanisms
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Mathias Ruiz, Aurélie Evrard, Vanna Géromel, Christine Lombard et al.
Orphanet Journal of Rare Diseases
Protease and Inhibitor Mechanisms
article

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

Mathias Ruiz, Aurélie Evrard, Vanna Géromel, Christine Lombard, Alexandre Fabre, Cyril Dourthe, Kai Markus Schneider, Aurélie Haffner, Carolin Victoria Schneider, Mathilde Butori-Pepino, Louis Lebreton, Sophie Collardeau‐Frachon, Céline Renoux, Jean‐William Dupuy, Philippe Joly, Radia Fritih, Marie‐Françoise Odou, Malika Balduyck, Bertrand Roquelaure, Anne‐Aurélie Raymond, Magali Dechomet, Marion Bouchecareilh, Victor Marin, Céline Léon, Sylvaine di-Tomasso, Emmanuelle Goubert
article en

Abstract

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<sub>marseille</sub>, results from in cis combination of the PiZ allele and a rare variant known as PiZ<sub>bristol</sub>. PiZ<sub>marseille</sub> 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<sub>marseille</sub> shares the pathogenic properties of both the PiZ and PiZ<sub>bristol</sub> 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<sub>marseille</sub> liver samples. Furthermore, when compared to other AAT genotypes, the proteomic profile of PiZ<sub>marseille</sub> most closely resembles that of the PiZ variant, rather than other SERPINA1 variants.

Orphanet Journal of Rare DiseasesVol. 20(1)
Centre National de la Recherche Scientifique (FR), Université de Bordeaux (FR), Inserm (FR), Aix-Marseille Université (FR), Université de Lille (FR), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Lille (FR), Hôpital Femme Mère Enfant (FR), Assistance Publique Hôpitaux de Marseille (FR), Hospices Civils de Lyon (FR), Bordeaux Population Health (FR), Hôpital Pellegrin (FR), Fondation Lenval (FR), Eurofins (France) (FR), Onco Lille (FR), Hôpital de la Timone (FR), Institut de Biologie de Lille (FR), RWTH Aachen University (DE)
Openalex Percentile: Top 57%
Protease and Inhibitor Mechanisms
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.