title: Deletion of Serpina1a, a murine α1-antitrypsin ortholog, results in embryonic lethality.
abstract: 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 α(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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wang
authors.forename: Weimin
authors.initials: W
authors.lastname: Wang
authors.forename: Paul
authors.initials: P
authors.lastname: Dawkins
authors.forename: Trevor
authors.initials: T
authors.lastname: Paterson
authors.forename: Noor
authors.initials: N
authors.lastname: Kalsheker
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Sallenave
authors.forename: A McGarry
authors.initials: AM
authors.lastname: Houghton
mesh_terms: D000825:Animal Structures / Q000166:cytology / Q000196:embryology; D000818:Animals; D020964:Embryo Loss; D047108:Embryonic Development; D005260:Female; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D011656:Pulmonary Emphysema / Q000235:genetics; D017384:Sequence Deletion; D015842:Serine Proteinase Inhibitors / Q000235:genetics; D015843:Serpins / Q000235:genetics; D000515:alpha 1-Antitrypsin / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics*
chemical_list: C043392:SERPINA1 protein, human; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D000515:alpha 1-Antitrypsin