A novel model and molecular therapy for Z alpha-1 antitrypsin deficiency.
- Resource Type
- Article
- Authors
- McNab, Gillian; Dafforn, Timothy; Wood, Alice; Sapey, Elizabeth; Stockley, Robert
- Source
- Mammalian Genome. Apr2012, Vol. 23 Issue 3/4, p241-249. 9p.
- Subject
- *ALPHA 1-antitrypsin deficiency
*LABORATORY mice
*POLYMERIZATION
*GENETIC disorders
*TRYPSIN inhibitors
*PULMONARY emphysema
*GENETICS
- Language
- ISSN
- 0938-8990
Animal models that closely resemble human disease can present a challenge. Particularly so in alpha-1 antitrypsin deficiency (αATD), as the mouse alpha-1 antitrypsin (αAT) cluster encodes five highly related genes compared with the one in humans. The mouse PI2 homologue is closest to the αAT human gene. We have changed the equivalent mouse site that results in the Z variant in man (Glu342Lys) and made both the 'M' and 'Z' mouse PI2 αAT proteins. We have tested the ability of a small-molecular-weight compound CG to alleviate polymerisation of these mouse αAT proteins as it has been shown to reduce aggregates of Z αAT in man. We found that (1) CG specifically reduces the formation of polymers of recombinant mouse 'Z' protein but not 'M' protein; (2) whereas there is significantly more αAT secreted from Chinese Hamster Ovary cells transfected with the mouse 'M' αAT gene than with the 'Z' (20.8 ± 3.9 and 6.7 ± 3.6, respectively; P < 0.005), CG increased the αAT levels secreted from 'Z' cells (21.2 ± 0.01) to that of 'M' (20.2 ± 0.02). The data support the concept that the murine 'Z' gene is a potential model for the study of αATD and that mice expressing this gene would be relevant for testing treatments in vivo. [ABSTRACT FROM AUTHOR]