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Title: The TRH-R in human endocrine disease : structure, function and characterisation
Author: Faccenda, Elena
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1997
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Genomic DNA from two unrelated patients suffering from isolated central hypothyroidism was screened for germline inactivating mutations. Patient 1 appeared to retain normal TRH-R sequence whereas, Patient 2 was found to have inherited a mutant TRH-R allele from each of his unaffected parents. Neither of the mutant TRH-Rs (M-STOP from the mother; F-TM3 from the father), when expressed in vitro, displayed TRH binding or therefore, second messenger function, explaining this patient's unresponsiveness to TRH administration. This is the first report of a naturally occurring mutation in a PLC- linked GPCR, and represents a novel cause of isolated central hypothyroidism. The affected patient appears to represent a naturally occurring TRH-R knock-out, a condition which due to the postulated various and widespread actions of TRH was presumed to be a lethal genetic condition. Generation of a transgenic mouse TRH-R knock-out model will allow more detailed analysis of the functions of TRH during embryogenesis and subsequent postnatal development, both in the brain and in extraneural locations. The results of the work described in this thesis indicate that the possession of inactivated TRH-Rs results in central hypothyroidism in one out of two randomly selected patients. It remains to be determined how prevalent such mutations may be in patients with this rare disorder and indeed in other congruous diseases. Patients presenting with other TSH-deficient conditions may reveal additional naturally occurring inactivating mutations. Site-directed mutagenesis of the hTRH-R has shown that substitution of a single amino acid within the receptor protein (Thr265 at the intron/exon boundary and within a site recognised as important for G-protein coupling) transforms it to a more active state. It is therefore feasible that such activating mutations of the hTHR-R may remain to be identified as underlying other abnormalities of the pituitary-thyroid axis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available