Characterization of a novel SERPINA1 variant carrying two missense mutations: molecular mechanisms and functional impact
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 PiZmarseille, results from in cis combination of the PiZ allele and a rare variant known as PiZbristol. PiZmarseille 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 PiZmarseille shares the pathogenic properties of both the PiZ and PiZbristol 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 PiZmarseille liver samples. Furthermore, when compared to other AAT genotypes, the proteomic profile of PiZmarseille most closely resembles that of the PiZ variant, rather than other SERPINA1 variants.
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BibTeX
@article{leon2026characterization,
title = {{Characterization of a novel SERPINA1 variant carrying two missense mutations: molecular mechanisms and functional impact}},
author = {Céline Léon and Marie-Françoise Odou and Bertrand Roquelaure and Louis Lebreton and Mathias Ruiz and Carolin Victoria Schneider and Céline Renoux and Aurélie Evrard and Malika Balduyck and Magali Dechomet and Christine Lombard and Mathilde Butori-Pepino and Kai Markus Schneider and Victor Marin and Sylvaine Di-Tomasso and Cyril Dourthe and Jean-William Dupuy and Anne-Aurélie Raymond and Sophie Collardeau-Frachon and Aurélie Haffner and Radia Fritih and Emmanuelle Goubert and Vanna Geromel and Philippe Joly and Alexandre Fabre and Marion Bouchecareilh},
journal = {Orphanet Journal of Rare Diseases},
year = {2026},
month = oct,
doi = {10.1186/s13023-025-04142-z},
url = {https://amu.hal.science/hal-05467117v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Characterization of a novel SERPINA1 variant carrying two missense mutations: molecular mechanisms and functional impact
AU - Céline Léon
AU - Marie-Françoise Odou
AU - Bertrand Roquelaure
AU - Louis Lebreton
AU - Mathias Ruiz
AU - Carolin Victoria Schneider
AU - Céline Renoux
AU - Aurélie Evrard
AU - Malika Balduyck
AU - Magali Dechomet
AU - Christine Lombard
AU - Mathilde Butori-Pepino
AU - Kai Markus Schneider
AU - Victor Marin
AU - Sylvaine Di-Tomasso
AU - Cyril Dourthe
AU - Jean-William Dupuy
AU - Anne-Aurélie Raymond
AU - Sophie Collardeau-Frachon
AU - Aurélie Haffner
AU - Radia Fritih
AU - Emmanuelle Goubert
AU - Vanna Geromel
AU - Philippe Joly
AU - Alexandre Fabre
AU - Marion Bouchecareilh
PY - 2026
DA - 2026/10/02
JO - Orphanet Journal of Rare Diseases
DO - 10.1186/s13023-025-04142-z
UR - https://amu.hal.science/hal-05467117v1
AB - 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 PiZmarseille, results from in cis combination of the PiZ allele and a rare variant known as PiZbristol. PiZmarseille 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 PiZmarseille shares the pathogenic properties of both the PiZ and PiZbristol 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 PiZmarseille liver samples. Furthermore, when compared to other AAT genotypes, the proteomic profile of PiZmarseille most closely resembles that of the PiZ variant, rather than other SERPINA1 variants.
SN - 1750-1172
ER -