S42 Characterizing ATP13A3 loss of function in pulmonary arterial hypertension (PAH)

Liu, B; Haimel, Matthias; Bleda, Marta; Li, W; Gräf, Stefan; Upton, PD; Morrell, NW

doi:10.1136/thorax-2018-212555.48

Cited by 3 publications

(4 citation statements)

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“…This includes pulmonary artery endothelial cells (PAECs), PASMCs, blood outgrowth endothelial cells (BOECs) [227] and human umbilical vein endothelial cells (HUVECs). PAH is characterised by molecular and cellular deviations in pulmonary vascular function [228,229], including hyperproliferation [124,129,130,149], impaired migration [127,130,150] and aberrant apoptosis [124,230]. Traditionally, research has focused on using 2D cellular monolayers for analysis of these features; however, with rapidly evolving technologies, future analysis may utilise multi-layer, 3D models such as organoids [231] and hydrogels [232] to better replicate the pathobiology of PAH.…”

Section: In Vitromentioning

confidence: 99%

“…The physiological impact of this mutation was assessed using whole-patch clamp tests to observe changes to membrane potential and current, with experiments demonstrating loss of channel function in mutant cells compared to WT KCNK3. More limited evidence is available for the role of ATP13A3, a P-type ATPase, in PAH; siRNA-mediated knockdown of expression resulted in a reduction in cell proliferation and increased apoptosis, as well as the loss of endothelial integrity in hPAECs [230]. Furthermore, mutant ATP13A3 mice, carrying a protein-truncating variant introduced using CRISPR/Cas9, demonstrated haemodynamic measurements indicative of PAH.…”

Section: Channelopathiesmentioning

confidence: 99%

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‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

Swietlik

Prapa

Martin

et al. 2020

Genes

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Although the invention of right heart catheterisation in the 1950s enabled accurate clinical diagnosis of pulmonary arterial hypertension (PAH), it was not until 2000 when the landmark discovery of the causative role of bone morphogenetic protein receptor type II (BMPR2) mutations shed new light on the pathogenesis of PAH. Since then several genes have been discovered, which now account for around 25% of cases with the clinical diagnosis of idiopathic PAH. Despite the ongoing efforts, in the majority of patients the cause of the disease remains elusive, a phenomenon often referred to as “missing heritability”. In this review, we discuss research approaches to uncover the genetic architecture of PAH starting with forward phenotyping, which in a research setting should focus on stable intermediate phenotypes, forward and reverse genetics, and finally reverse phenotyping. We then discuss potential sources of “missing heritability” and how functional genomics and multi-omics methods are employed to tackle this problem.

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Section: In Vitromentioning

confidence: 99%

Section: Channelopathiesmentioning

confidence: 99%

‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

Swietlik

Prapa

Martin

et al. 2020

Genes

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“…and ATP13A3 as genes which may be responsible for these effects. CDH13 is a regulator of vascular wall remodelling and angiogenesis 44 , and ATP13A3 has recently been implicated in pulmonary arterial hypertension susceptibility through rare loss of function analyses 45,46 . However, although there are likely many instances where integrating tissue-specific eQTL data can help pinpoint genes responsible for GWAS associations, this may not always be possible due to the complexities of coexpression and widely expressed genes 47 .…”

Section: Discussionmentioning

confidence: 99%

A transcriptome-wide Mendelian randomization study to uncover tissue-dependent regulatory mechanisms across the human phenome

et al. 2020

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Developing insight into tissue-specific transcriptional mechanisms can help improve our understanding of how genetic variants exert their effects on complex traits and disease. In this study, we apply the principles of Mendelian randomization to systematically evaluate transcriptome-wide associations between gene expression (across 48 different tissue types) and 395 complex traits. Our findings indicate that variants which influence gene expression levels in multiple tissues are more likely to influence multiple complex traits. Moreover, detailed investigations of our results highlight tissue-specific associations, drug validation opportunities, insight into the likely causal pathways for trait-associated variants and also implicate putative associations at loci yet to be implicated in disease susceptibility. Similar evaluations can be conducted at http://mrcieu.mrsoftware.org/Tissue_MR_atlas/.

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“…ATP13A3 knockdown in PAECs reduces cell proliferation, predisposes to early apoptosis and increases permeability 52 . Still, ATP13A3 function and substrate remain elusive.…”

Section: State Of the Artmentioning

confidence: 99%

The role of genomics and genetics in pulmonary arterial hypertension

Swietlik¹,

Gräf²,

Morrell³

2020

gcsp

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[No abstract. Showing first paragraph of article]Although pulmonary hypertension (PH) had been recognised for centuries, it was not until the invention of cardiac catheterisation in the 1950s that enabled an accurate gene encoding bone morphogenetic protein receptor type 2, in patients with familial and clinical diagnosis. The discovery of heterozygous germline mutations in BMPR2, the idiopathic forms of pulmonary arterial hypertension (PAH) was another breakthrough in understanding the disease and initiated a new era in care of patients with this condition.

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S42 Characterizing ATP13A3 loss of function in pulmonary arterial hypertension (PAH)

Cited by 3 publications

References 0 publications

‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

A transcriptome-wide Mendelian randomization study to uncover tissue-dependent regulatory mechanisms across the human phenome

The role of genomics and genetics in pulmonary arterial hypertension

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