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A combined in silico and in vitro study on mouse Serpina1a antitrypsin-deficiency mutants.
Eggenschwiler, Reto Patronov, Atanas Hegermann, Jan Fráguas-Eggenschwiler, Mariane Wu, Guangming Cortnumme, Leon Ochs, Matthias Antes, Iris Cantz, Tobias
Eggenschwiler, Reto
Patronov, Atanas
Hegermann, Jan
Fráguas-Eggenschwiler, Mariane
Wu, Guangming
Cortnumme, Leon
Ochs, Matthias
Antes, Iris
Cantz, Tobias
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2019-05-16
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Abstract
Certain point-mutations in the human SERPINA1-gene can cause severe α1-antitrypsin-deficiency (A1AT-D). Affected individuals can suffer from loss-of-function lung-disease and from gain-of-function liver-disease phenotypes. However, age of onset and severity of clinical appearance is heterogeneous amongst carriers, suggesting involvement of additional genetic and environmental factors. The generation of authentic A1AT-D mouse-models has been hampered by the complexity of the mouse Serpina1-gene locus and a model with concurrent lung and liver-disease is still missing. Here, we investigate point-mutations in the mouse Serpina1a antitrypsin-orthologue, which are homolog-equivalent to ones known to cause severe A1AT-D in human. We combine in silico and in vitro methods and we find that analyzed mutations do introduce potential disease-causing properties into Serpina1a. Finally, we show that introduction of the King’s-mutation causes inactivation of neutrophil elastase inhibitory-function in both, mouse and human antitrypsin, while the mouse Z-mutant retains activity. This work paves the path to generation of better A1AT-D mouse-models.
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Sci Rep. 2019 May 16;9(1):7486. doi: 10.1038/s41598-019-44043-3.
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2045-2322
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Attribution-NonCommercial-ShareAlike 4.0 International