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Title: Study of MeCP2 function in a mouse model of Rett syndrome
Author: Kriaucinonis, S.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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It is now commonly agreed that Rett Syndrome is a monogenic neurological disease caused by mutations in MECP2 gene. Rett Syndrome mainly occurs in girls and it is characterised by a period of normal development until around 6­18 months, followed by a rapid regression. After the regression, symptoms persist as severe mental retardation, reduced head size, seizures, ataxia, hyperventilation and repetitive hand wringing movements. The phenotype of mice with a deleted Mecp2 gene mimics some Rett Syndrome symptoms. The Mecp2­null mouse develops normally until about 6 weeks of age after which tremors, irregular breathing, lack of mobility and hindlimb clasping develop. To understand how the lack of MeCP2 causes Rett Syndrome, the search for MeCP2 regulated genes was initiated in Mecp2-null mouse brain. Examination of candidate genes revealed that Bdnf is down-regulated and Hes1 is up-regulated in pre, early and late symptomatic Mecp2-null mice. Further, global analysis of gene expression was examined by ADDER differential display. Some mis-regulated genes were identified, two of which are involved in mitochondrial respiration. Oxygen electrode measurements revealed defects in brain mitochondrial respiration, which commenced coincident with symptom onset in Mecp2-null mice. This finding suggests mitochondrial involvement in the pathogenesis of Rett Syndrome symptoms. In the course of these studies, the structure of the Mecp2 gene was re-investigated, leading to the identification of a new MeCP2 isoform. Data in this thesis demonstrates that the new isoform is the major form of MeCP2 in both mouse and human brain.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available