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Développement d'une stratégie de criblage du gène MECP2 chez des patientes atteintes d'un syndrôme de Rett : mise en évidence d'un spectre hétérogène de mutations

Abstract : Ret! syndrome (RTT) IS a progressIVe neurodevelopmentaI disorder affecting almost exclusively females with an incidence of 1 in 15,000. Defined by accurate clinical criteria, RTT is characterized by a period of early normal growth and development followed by regression with loss of speech and acquired motor skills, stereotypical hand movements, and seizures. Althougb 99,5% of cases are sporadic, exclusion mapping using rare familial cases allowed the assignment of the gene responsable for RTT to Xq28. Systematic mutation analysis of candidate genes in the critical region resulted in the identification of mutations in the MECP2 gene. During this work, we carried out a mutation analysis of MECP2 gene in 255 females with RTT and 15 mentally retarded boys. To identify MECP2 mutations, we developped several complementary approaches (FISH, Southem blot, semi-quantitative PCR, CSGE-sequencing, then DHPLC-sequencing) and provided insights into an heterogeneous spectrum of mutations at the MECP2 locus in RTT patients. Accordingly, we showed that in addition of point mutations, rearrangements involving several hundreds base pairs can be detected. Moreover and for the first time in RTT girls, we reported cases of somatic mosaicism. Finally, a study at the chromosome level of the MECP2 gene did not reveal any deletion in RTT patients. We found 79% of mutations in RTT patients, our mutation detection rate is in agreement with the Iiterature data. Our mutation screening strategy of the ]MECP2 gene is an essential molecular diagnosis tool to confirm the c1inical diagnosis. The link between MECP2 function (global repressor of methylated genes transcription) and disease expression is still unknoWll. Many studies are necessary to understand thephysiological mechanism leading to RTT and eventually to develop therapeutic strategies.
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https://hal.univ-lorraine.fr/tel-01748672
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Violaine Bourdon. Développement d'une stratégie de criblage du gène MECP2 chez des patientes atteintes d'un syndrôme de Rett : mise en évidence d'un spectre hétérogène de mutations. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2002. Français. ⟨NNT : 2002NAN10292⟩. ⟨tel-01748672⟩

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