Deletion of serpina1a, a murine alpha(1)-antitrypsin ortholog, results in embryonic lethality

D.M. Wang, W.M. Wang, P. Dawkins, T. Paterson, N. Kalsheker, J.M. Sallenave, A.M. Houghton

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States Approximately 1% to 2% of COPD patients suffer from alpha(1)-antitrypsin (A1AT) deficiency, the major inheritable predisposition to COPD/emphysema. To further study the role of A1AT deficiency in the pathogenesis of COPD/emphysema, the authors attempted to generate null-mutant mice for Serpina1a, 1 of 2 A1AT orthologs in mice. Here the authors show that targeted deletion of Serpina1a results in embryonic lethality prior to 8.5 days post conception (dpc). The results are surprising given that A1AT-null humans exist and therefore do not require this gene product for normal development. The Serpina1 gene cluster is substantially different between mouse and man. Through gene duplication, mice have 3 to 5 (depending on the strain) highly homologous proteinase inhibiting (Pi) genes, 2 of which inhibit neutrophil elastase. Despite the abundance of Pi genes in mice, Serpina1a serves a critical, nonredundant function during early mouse development. A1AT-deficient mice have been highly sought after to study emphysema, cancer, and liver disease, and as a model to perfect gene replacement therapy. These results highlight important differences between human and murine serpins and point to the difficulty inherent to using gene-targeted mice to study this common human genetic disease.
Original languageUndefined/Unknown
Pages (from-to)291-300
Number of pages10
JournalExperimental Lung Research
Issue number5
Publication statusPublished - 2011

Keywords / Materials (for Non-textual outputs)

  • A1AT COPD Serpins alpha-1-antitrypsin deficiency neutrophil elastase alpha1-antitrypsin deficiency pulmonary-emphysema tight-skin protease inhibitors genetic emphysema mice mouse expression

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