Construction of Animal Models of Human Disorders by Injection of Large Genomic Fragment: From Function to Physiopathology and Therapy

Michel Fontes
INSERM U491
Medical genetics and Development
Fac de Médecine de la Timone
Marseille, France
telephone: +33 4 91 25 71 59
fax: +33 4 91 80 43 19
email: fontes@medecine.univ-mrs.fr
prestype: Platform
presenter: Michel Fontes

E. Passage1, Sanguedolce V.1, J. Pizant1, J.F. Pellissier2 and M. Fontés1
1INSERM U491, Medical genetics and Development, Fac de Médecine de la Timone, Marseille, France
2Laboratoire de Biopathologie Nerveuse et Musculaire, Fac de Médecine de la Timone, Marseille, France

A major challenge of functional genomic is to understand the function of genes which have been characterized through the human genome sequencing effort. This goal is particularly important in medical genetics, as we did not know (or poorly) the function of genes, cloned through positional cloning strategies, and involved in inherited disorders. We have thus developed the construction of animal models in order to understand the function in normal and pathological conditions of inherited disorders. Moreover, these models can also be used as"preclinical models", in order to test new therapeutical approaches. We have used a new approach to create these models: a transgenic strategy using large cloned genomic fragments (YAC, PAC, BAC) which present the following advantages: One would expect there to be stable expression which. The use of standard methods results in a low level of transgene expression. In contrast, however, several experiments carried out using large fragments of DNA have shown expression levels similar to those found for endogenous copies. The control of transgenic expression should perfectly reproduce that of the endogene. Another advantage of this approach is that expression is not dependent on the site of integration.

Using this strategy, we have constructed two models: one for the Charcot-Marie-Tooth type 1A (CMT1A) disorder and one for the Creutzfeld-Jacob disorder. The construction of a model for PKD1 is in progress. From these models we have already gained important insights in the physiopathological processes involved in these disorders. Two examples will be given. CMT1A disorder is not a demyelinating disorder but a dysmyelinating disease, giving us some clue to the function of the gene PMP22 involved in the disorder. Overexpression of the prion protein, did not affect the development of the central nervous system. Finally, we will present our strategy to test molecules that seems to revert the phenotype.



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