Disruption of the adenosine deaminase (ADA) gene using a dicistronic promoterless construct: Production of an ADA-deficient homozygote ES cell line View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

1995-07

AUTHORS

Sophie Vaulont, Sam Daines, Martin Evans

ABSTRACT

In man, deficiency of ADA activity is associated with an autosomal recessive form of severe combined immunodeficiency (SCID), a disease with profound defects both cellular and humoral immunity. Current treatments of ADA deficient patients include bone marrow transplantation, enzyme replacement and somatic gene therapy. The mechanism of the selective immune cell pathogenesis in ADA-SCIDS is, however, still poorly understood. Thus, the generation of an ADA deficient mouse model will be of considerable benefit to understand better the pathophysiology of the disorder and to improve the gene therapy treatments. We have disrupted the adenosine deaminase (ADA) gene in embryonic stem cells using a new efficient promoter trap gene-targeting approach. To this end, a dicistronic targeting construct containing a promoterless IRES beta geo cassette was used. This cassette allows, via the internal ribosomal entry site (IRES), the direct cap-independent translation of the beta geo reporter gene which encodes a protein with both beta-galactosidase and neomycin activities. After indentification of targeted clones by Southern blot, successful inactivation of the ADA gene was first confirmed by producing, from our heterozygote clones, an homozygote cell line. This line shows no ADA activity as judged by zymogram analysis. Second, we have been able to detect in the targeted clones, a specific beta galactosidase activity using a sensitive fluorogenic assay. The targeted ES cell clones are currently being injected into blastocysts to create an ADA deficient mouse model. More... »

PAGES

247-255

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/bf01969118

DOI

http://dx.doi.org/10.1007/bf01969118

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/7655514


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