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https://hdl.handle.net/2440/140026
Type: | Thesis |
Title: | Defining The Role of a Novel Gene “MyoD Family Inhibitor Domain Containing (MDFIC)” Important in Cardiovascular Development |
Author: | Montazaribarforoushi, Saba |
Issue Date: | 2023 |
School/Discipline: | Adelaide Medical School |
Abstract: | Central conducting lymphatic anomaly (CCLA), characterised by dysfunction of core collecting lymphatic vessels including the thoracic duct and cisterna chyli, often manifests in utero as non-immune hydrops fetalis (NIHF) (also known as foetal hydrops). Clinical presentation of CCLA may also include chylothorax, pleural effusions, chylous ascites or lymphoedema, and is a severe disease for which few effective treatments are available. The genetic aetiology of CCLA remains uncharacterised in the majority of cases. Here, by exploring the genetics underlying lymphatic vascular disorders, we identified seven affected individuals in six independent families with CCLA in whom biallelic variants in MDFIC, encoding the MyoD family inhibitor domain containing protein, were identified. Generation of a mouse model of a recurrent human MDFIC truncating variant (Met131Asnfs*3) revealed that MdficM131fs*/M131fs* homozygous mutant mice died perinatally exhibiting chylothorax with accumulation of lipid rich chyle in the thoracic cavity. The lymphatic vasculature of these mice was profoundly mis-patterned, particularly in the diaphragm and thoracic wall, and exhibited defects in lymphatic vessel valve development. This work is the first to identify pathogenic MDFIC variants underlying human lymphatic vascular disease and reveals that MDFIC plays a pivotal role in the development of lymphatic vessel valves. Mechanistically, we demonstrate that the cysteine-rich C-terminus of MDFIC, which is absent in the MDFIC p.Met131fs* truncated protein, is essential for interaction with GATA2, a transcription factor with an essential role in lymphatic vessel valve development. Alteration in GATA2 subcellular localisation and transcriptional activity within cells in a setting of MDFIC deficiency was detected. Our preliminary data also suggest that biallelic truncating MDFIC variants in patients exhibiting CCLA increases MAPK/ERK signalling activity, raising the question as to whether the dampening activity of this pathway might provide a therapeutic opportunity for the treatment of CCLA caused by MDFIC variants. Future work aims to characterise the mechanisms by which MDFIC controls the activity of GATA2 and RAS/MAPK signalling in the lymphatic vasculature and to investigate the efficacy of small molecule inhibitors of GATA2 and RAS/MAPK signalling in rescuing the symptoms and lethality of CCLA in our novel genetic mouse model of this disease. |
Advisor: | Scott, Hamish Harvey, Natasha (Centre for Cancer Biology, University of South Australia) |
Dissertation Note: | Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2023 |
Keywords: | Genetics development MDFIC lymphatic |
Provenance: | This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals |
Appears in Collections: | Research Theses |
Files in This Item:
File | Description | Size | Format | |
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Montazaribarforoushi2023_PhD.pdf | 22.09 MB | Adobe PDF | View/Open |
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