Unknown

Dataset Information

0

A combined in silico and in vitro study on mouse Serpina1a antitrypsin-deficiency mutants.


ABSTRACT: Certain point-mutations in the human SERPINA1-gene can cause severe ?1-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.

SUBMITTER: Eggenschwiler R 

PROVIDER: S-EPMC6522476 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

altmetric image

Publications

A combined in silico and in vitro study on mouse Serpina1a antitrypsin-deficiency mutants.

Eggenschwiler Reto R   Patronov Atanas A   Hegermann Jan J   Fráguas-Eggenschwiler Mariane M   Wu Guangming G   Cortnumme Leon L   Ochs Matthias M   Antes Iris I   Cantz Tobias T  

Scientific reports 20190516 1


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 l  ...[more]

Similar Datasets

| S-EPMC2633144 | biostudies-literature
| S-EPMC3496730 | biostudies-literature
2020-12-08 | GSE109516 | GEO
2020-11-03 | GSE109515 | GEO
| S-EPMC6147237 | biostudies-other
| S-EPMC5956786 | biostudies-literature
| S-EPMC5925576 | biostudies-literature
| S-EPMC5296240 | biostudies-literature
| S-EPMC4957051 | biostudies-literature
| S-EPMC5106446 | biostudies-literature