Recherche de gènes candidats responsables d'anomalies du développement grâce à la caractérisation moléculaire de microremaniements chromosomiques

Abstract : Positional candidate gene approach and molecular characterization of chromosomal abnormalities can elucidate the genetic basis of many human developmental diseases. Mapping of such rearrangements allows the identification of disease candidate genes by using cytogenetic and molecular biology approaches. Array-CGH serves the critical need for identification of causal genes related to disease by detection of unknown chromosomal imbalances.We report here the results of mapping and molecular characterization of two unbalanced chromosomal rearrangements related to mental retardation : 20q13.33 and 21q21 deletions. This study led to candidate genes identification and contributed to improve clinical monitoring and genetic counseling.Moreover, the breakpoints characterization of a balanced de novo translocation t(3;18)(p12.3;q23) associated with an early-onset generalized dystonia and developmental delay revealed the disruption of ROBO1, a gene mediating axone guidance. Additional analysis including array-CGH, RNA and protein analysis, leukocyte chemotaxis and search for ROBO1 mutations in 20 independent patients with syndromic dystonia were performed in order to evaluate the correlation beetween ROBO1 disruption and dystonia. The results presented here underline the difficulties in elucidating the role of such rearrangements, and the need to provide further evidences in defining their involvment in the development of a genetic disease.
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Mylène Béri. Recherche de gènes candidats responsables d'anomalies du développement grâce à la caractérisation moléculaire de microremaniements chromosomiques. Sciences agricoles. Université Henri Poincaré - Nancy 1, 2009. Français. ⟨NNT : 2009NAN10141⟩. ⟨tel-01748566⟩

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