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Title: Application of a Drosophila melanogaster model to study Familial Isolated Pituitary Adenomas syndrome pathogenesis in vivo
Author: Aflorei, Elena Daniela
ISNI:       0000 0004 7962 3779
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2016
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A phenotypically distinct subgroup of familial isolated pituitary adenoma (FIPA) families has mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene leading to young-onset acromegaly in most patients. These patients typically develop invasive pituitary adenomas, but the mechanisms by which AIP inactivation promotes pituitary tumorigenesis and an aggressive behaviour remain unknown. To date, more than 70 different AIP variants have been reported and determining the pathogenicity of missense variants is a challenging problem. The Drosophila AIP orthologue (CG1847) is located on the X chromosome and encodes a protein of similar size and structure to human protein (hAIP). I have generated CG1847 deficient flies via two methods: in vivo RNAi knockdown and imprecise excision of a transposable P-element, which generated a putative null allele of CG1847. Our data show that knockdown and knockout of CG1847 results in lethality confirming that AIP is an essential gene. To reveal the potential underlying molecular mechanisms of loss of AIP, a whole transcriptome analysis was performed in mutant versus control male larvae. This allowed us to determine gene expression profiles and to identify key pathways that are significantly altered in the mutant, and that are related to embryonic development or survival. To functionally test the homology between hAIP and CG1847, I used the Gal4/UAS system to perform rescue experiments. I subsequently tested whether wild-type hAIP, a truncated hAIP and four missense mutations identified in FIPA families could rescue the lethality of CG1847exon1_3 mutants by expressing hAIP during fly development. In this thesis were identified novel AIP features. CG1847 is a Drosophila melanogaster AIP orthologue and is essential for normal development. RNA sequencing revealed possible new underlying CG1847 molecular mechanisms as the tumour suppressor function of AIP might involve the regulation of cytoskeletal organisation. Drosophila is a useful in vivo system to study human AIP missense variants to establish pathogenicity.
Supervisor: Not available Sponsor: William Harvey Research Foundation ; European Society of Endocrinology
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pituitary adenoma ; Aryl hydrocarbon receptor interacting protein gene