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Title: The genetic basis of severe early-onset obesity and developmental delay
Author: Gray, J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2007
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The neurotrophin receptor, tropomyosin related kinase B (TrkB), and its ligand, brain-derived neurotrophic factor (BDNF), are involved in neuronal development and synaptic plasticity and genetic models of disruption in rodents result in severe obesity. I screened the genes encoding TrkB (NTRK2) and BDNF for potential pathogenic mutations in 373 subjects with severe early onset obesity and developmental delay. I identified five rare NTRK2 mutations, three of which were in highly conserved residues and were therefore characterised functionally. Using assays of ligand induced phosphorylation and signalling, the variants were not found to be functionally impaired. No rare sequence variants were identified in BDNF, but a previously reported common polymorphism (Val66Met) was identified and association studies in two large UK Caucasian population based cohorts were performed. No significant associations with body mass index were identified. We identified a patient with severe obesity and a distinct neurobehavioral phenotype who harboured a de novo chromosomal inversion (46,XX,inv(11)(p13p15.3)), a region encompassing the BDNF locus. Using a combination of cytogenetic and molecular analyses, I characterised the proximal breakpoint of the inversion, mapping it to ~850kb upstream of BDNF. I demonstrated monoallelic expression and reduced serum BDNF levels consistent with BDNF haploinsufficiency, providing the first direct evidence for the role of BDNF in human energy balance. I genotyped two further genes, TUB and ATP10a; no pathogenic mutations were identified. I used microarray-based Comparative Genomic Hybridisation to identify unique copy number variants in patients with severe early-onset obesity and developmental delay with a normal karyotype.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available