Construction pour une souris modèle du syndrome "Seckel” humain

Using Red/ET recombination a targeting construct for a model of “Seckel” syndrome characterized by a severe deficiency in ATR was generated. Usually ATR kinase (Ataxia Telangiectasia and Rad3-related serine/threonine-protein kinase) prevents replicative stress, a source of endogenous DNA damage. A point mutation in exon 9 was thought to be responsible for an incorrect slicing of the mRNA, which results in a deletion of exon 9. The animal model based on the constructs given below confirmed this hypothesis.


Voir tous les Kits de recombinaison Red/ET :

Cloning strategy: 1. Replacement of entire mouse genomic fragment encompassing exon 8, 9 and 10 of ATR gene, with human counterpart; 2. Introduction of “Seckel” mutation into humanized mouse allele (nucleotide exchange from adenine to guanine)

Final targeting construct for ES cell recombination generated by Gene Bridges

Analysis of the mouse model: “Seckel” mice show high levels of replicative stress during embryogenesis, when proliferation is widespread, but this is reduced to marginal amounts in postnatal life. In spite of this decrease, adult “Seckel” mice show accelerated aging, which is further aggravated in the absence of p53. Together, these results support a model whereby replicative stress, particularly in utero, contributes to the onset of aging in postnatal life, and this is balanced by the replicative stress–limiting role of the checkpoint proteins ATR and p53.