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| Status |
Public on May 07, 2024 |
| Title |
FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Genetic variation in FLT4 is associated with the most prevalent cyanotic congenital heart disease,Tetralogy of Fallot (TOF). Distinct genetic variation in FLT4 is an established cause of Milroy disease, the prevailing form of primary hereditary lymphoedema. Phenotypic features of the conditions are non-overlapping, implying pleiotropic mechanisms. Here, TOF-associated FLT4 variants identified in patients,aggregate in the perinuclear/secretory pathway, activating proteostatic/metabolic signalling that lymphoedema-associated FLT4 variants do not. FLT4 TOF variants display characteristic gene expression changes in developmental signalling pathways, when expressed in undifferentiated human endothelial cells, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of the main pathways of proteostasis abrogates these effects, identifying potential avenues for therapeutic intervention. We show that a gain-of-pathogenic-function mechanism causes TOF, contrasting with the dominant negative mechanism identified for Milroy-causative variants.This is among the first demonstrations that mechanistically elucidates developmental pleiotropy of thevascular system.
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| Overall design |
We performed gene expression analysis using data obtained from RNA-seq of FLT4 WT and FLT4 genes containing variants associated with both TOF and Milroy disease (MD).
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| Web link |
https://academic.oup.com/cardiovascres/advance-article/doi/10.1093/cvr/cvae104/7666260?utm_source=advanceaccess&utm_campaign=cardiovascres&utm_medium=email
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| Contributor(s) |
Monaghan RM, Naylor RW, Flatman D, Kasher PR, Williams SG, Keavney BD |
| Citation(s) |
38713105 |
| |
| Submission date |
May 26, 2022 |
| Last update date |
Aug 18, 2024 |
| Contact name |
Simon Williams |
| E-mail(s) |
simon.williams2@manchester.ac.uk
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| Organization name |
The University of Manchester
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| Street address |
Oxford Road
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| City |
Manchester |
| ZIP/Postal code |
M13 9PT |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA842706 |
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