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Title: Signal transduction defects in the human syndromes of severe insulin resistance
Author: George, S.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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This thesis describes the characterization of several mutations found in subjects with severe insulin resistance. The first mutation was found in an infant with the most severe type of insulin resistance-Donohue’s syndrome. This mutation (DV335) in the insulin receptor was found to cause abnormal processing such that only 30% of mature receptor was formed when compared to wild type. A mutation (E1092Q) in the cyclic GMP inhibited phosphodiesterase PDE3B was found in a patient with type A insulin resistance. Involved in the anti-lipolytic actions of insulin, the activation of PDE3B results in a decrease in free fatty acid release upon insulin stimulation. However, upon genotyping of several members of the pedigree it was found that the mutation did not clearly co-segregate with insulin resistance. Two different mutations were identified in three separate pedigrees in the gene coding for Son of Sevenless (SOS1). N1011S was found in two pedigrees, and V128I was found in the third. Genotyping and basic phenotyping was carried out on all available members from these three pedigrees. Unfortunately, this failed to reveal a co-segregation of the mutations with severe insulin resistance. Finally, a mutation (R274H) in AKT2/PKBb was found to co-segregate with severe insulin resistance in 4 members of a pedigree. Studies showed that the mutation caused the protein to be kinase inactive and to act in a dominant negative manner over both AKT1 and AKT2. Detailed physiological studies of one member confirmed her severe insulin resistance as well as revealing her lipodystrophy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available