FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms
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ABSTRACT:
PROVIDER: PRJNA842706 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19419421_1.fastq.gz | Fastqsanger.gz | |||
| SRR19419421_2.fastq.gz | Fastqsanger.gz | |||
| SRR19419422_1.fastq.gz | Fastqsanger.gz | |||
| SRR19419422_2.fastq.gz | Fastqsanger.gz | |||
| SRR19419423_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
2024-05-07 | GSE204910 | GEO
Project description:AimsRare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease. The distinct genetic variants in FLT4 are also an established cause of Milroy disease, the most prevalent form of primary hereditary lymphoedema. The phenotypic features of these two conditions are non-overlapping, implying pleiotropic cellular mechanisms during development.Methods and resultsIn this study, we show that FLT4 variants identified in patients with TOF, when expressed in primary human endothelial cells, cause aggregation of FLT4 protein in the perinuclear endoplasmic reticulum, activating proteostatic and metabolic signalling, whereas lymphoedema-associated FLT4 variants and wild-type (WT) FLT4 do not. FLT4 TOF variants display characteristic gene expression profiles in key developmental signalling pathways, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of proteostatic signalling abrogates these effects, identifying potential avenues for therapeutic intervention. Depletion of flt4 in zebrafish caused cardiac phenotypes of reduced heart size and altered heart looping. These phenotypes were rescued with coinjection of WT human FLT4 mRNA, but incompletely or not at all by mRNA harbouring FLT4 TOF variants.ConclusionTaken together, we identify a pathogenic mechanism for FLT4 variants predisposing to TOF that is distinct from the known dominant negative mechanism of Milroy-causative variants. FLT4 variants give rise to conditions of the two circulatory subdivisions of the vascular system via distinct developmental pleiotropic molecular mechanisms.
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Project description:Single cell, whole embryo phenotyping of pleiotropic disorders of mammalian development
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Project description:Lameness is an animal welfare issue that incurs substantial financial and environmental costs. This condition is commonly caused by digital dermatitis (DD), sole ulcers (SU), and white line disease (WLD). Susceptibility to these three foot disorders is due in part to genetics, indicating that genomic selection against these foot lesions can be used to reduce lameness prevalence. It is unclear whether selection against foot lesions will lead to increased susceptibility to other common diseases such as mastitis and metritis. Thus, the aim of this study was to determine the genetic correlation between causes of lameness and other common health disorders to identify loci contributing to the correlation. Genetic correlation estimates between SU and DD and between SU and WLD were significantly different from zero (P < 0.05), whereas estimates between DD and mastitis, DD and milk fever, and SU and metritis were suggestive (P < 0.1). All five of these genetic correlation estimates were positive. Two-trait genome-wide association studies (GWAS) for each of these five pairs of traits revealed common regions of association on BTA1 and BTA8 for pairs that included DD or SU as one of the traits, respectively. Other regions of association were unique to the pair of traits and not observed in GWAS for other pairs of traits. The positive genetic correlation estimates between foot disorders and other health disorders imply that selection against foot disorders may also decrease susceptibility to other health disorders. Linkage disequilibrium blocks defined around significant and suggestive SNPs from the two-trait GWAS included genes and QTL that were functionally relevant, supporting that these regions included pleiotropic loci.
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Project description:A meta-genome-wide association study across eight psychiatric disorders has highlighted the genetic architecture of pleiotropy in major psychiatric disorders. However, mechanisms underlying pleiotropic effects of the associated variants remain to be explored. We conducted a massively parallel reporter assay to decode the regulatory logic of variants with pleiotropic and disorder-specific effects. Pleiotropic variants differ from disorder-specific variants by exhibiting chromatin accessibility that extends across diverse cell types in the neuronal lineage and by altering motifs for transcription factors with higher connectivity in protein-protein interaction networks. We mapped pleiotropic and disorder-specific variants to putative target genes using functional genomics approaches. In vitro CRISPR perturbation of selected variants confirmed the variant-gene relationships, and in vivo CRISPR perturbation of a pleiotropic and a disorder-specific gene suggests that pleiotropy may involve regulation of genes expressed broadly across neuronal cell types and with higher network connectivity.
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Project description:A meta-genome-wide association study across eight psychiatric disorders has shed light on the genetic architecture of pleiotropy in major psychiatric disorders. However, the mechanisms underlying pleiotropic effects of the associated variants remain to be investigated. We conducted a massively parallel reporter assay to decipher the regulatory logic of variants with disorder-specific and pleiotropic effects. We found that pleiotropic variants differ from disorder-specific variants by manifesting chromatin accessibility that extends across diverse cell types in the neuronal lineage, as well as by altering motifs for transcription factors with higher connectivity in protein-protein interaction networks. Next, we mapped pleiotropic and disorder-specific variants to putative target genes using functional genomics approaches. CRISPR-mediated validation confirmed the functional impact of selected variants on predicted target genes. Furthermore, in vivo CRISPR perturbation of a pleiotropic and a disease-specific gene suggests that pleiotropy is mediated by the regulation of genes expressed in a broader range of neuronal types and with higher network connectivity.
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