Abstract
[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.
Highlights
Pulmonary hypertension (PH) had been recognised for centuries, it was not until the invention of cardiac catheterisation in the 1950s that enabled an accurate clinical diagnosis1
In clinically diagnosed ‘‘idiopathic’’ pulmonary arterial hypertension (PAH) cohorts, up to 25% of patients have mutations in known PAH risk genes, leaving the remaining 75% without explanation about the disease trigger and pathobiology
Environmental factors may account for some of these idiopathic cases, it seems likely that additional, unknown, rare genetic variation is responsible for many more cases
Summary
Pulmonary hypertension (PH) had been recognised for centuries, it was not until the invention of cardiac catheterisation in the 1950s that enabled an accurate clinical diagnosis. Exome sequencing of individuals without deleterious variants in BMPR2, but with more than one family member diagnosed with PAH revealed mutations in caveolin-1, encoded by CAV1, which participates in colocalisation of BMP receptors. Further screening of initial and validation cohort identified deleterious, heterozygous, missense variants in patients with IPAH, familial PAH, and PAH associated with congenital heart disease. Functional studies confirmed the decreased activity of the ATP-sensitive potassium channel, adding evidence to the theory that a subset of PAH patients might be mechanistically described as having potassium channelopathy51 Further support for this hypothesis came from the NBR study in PAH, which reported an association between rare deleterious variants in ATP13A3 and AQP1 and PAH8. EIF2AK4, known as general control non-depressible 2 (GCN2), encodes a serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic initiation factor 2, which plays a key role in modulation amino acid metabolism in response to nutrient deprivation
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