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Characterisation of two new mouse models of neurodegenerative diseases

Achilli, F; (2007) Characterisation of two new mouse models of neurodegenerative diseases. Doctoral thesis , UCL (University College London). Green open access

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The aim of this study was to phenotypically and genotypically characterize two new neurological mouse mutants arising from the Harwell ENU Mutagenesis Programme. GENA 201 and 202 mice are siblings. Heterozygous mice show poor grip strength and have a dominantly inherited phenotype. Homozygotes show compromised hind limb movement resulting in a more severe phenotype. Histopathology data from 15 days old GENA201 and 202 homozygotes showed a significantly reduced dorsal column in thoracic spinal cord sections. To identify the mutant gene underlying the GENA201 and 202 phenotypes, mutant backcross progeny were genotyped with a panel of markers spanning the genome. Both GENA 201 and 202 mutations were localised to a 5Mb region on chromosome 6 suggesting they are allelic. A point mutation (T>C transition in exon 5) was identified in the glycyl tRNA synthetase gene in both mouse lines, which charges tRNA with glycine. Glycyl tRNA synthetase mutations have been identified in two hereditary motor and sensory neuropathies, Charcot Marie Tooth 2D and distal spinal muscular atrophy type V, thus the gene plays a role in neurological diseases. GENA 201 and 202 mutants are therefore interesting animal models that could provide new insights in the understanding of new biological pathways involved in hereditary motor and sensory neuropathies. To investigate the possible functional impact of the mutation, a protein assay was carried out. No loss of glycyl tRNA activity was observed by comparing Gar C201RI+ with wild type littermates. However, a reduction in activity was observed in Gar C207R/C201R mice compared to wild type and Gar C201RI+ littermates suggesting that the possible molecular mechanisms of pathology for the GarsC201R mutation might be some loss of function. In addition to GENA 201 and 202 lines, the BHV7 mouse line was also characterised. BHV7 heterozygote mice are significantly lighter than wild types and show an ataxic gait with retropulsion. Histopathology data from 6 month old BHV7 mutant mouse brain also revealed cerebellar defects characterized by loss of Purkinje cells. BHV7 is of potential interest for the study of ataxia. Genotyping of BHV7 mutants localised the mutation to a 26 Mb interval on chromosome 3. The two mutations are valuable additions to the scientific community and may be useful in the better understanding of the genetic basis of neurodegenerative diseases.

Type: Thesis (Doctoral)
Title: Characterisation of two new mouse models of neurodegenerative diseases
Identifier: PQ ETD:593636
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity.
URI: https://discovery.ucl.ac.uk/id/eprint/1446294
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