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Cambridge Institute for Medical Research


Pulmonary arterial hypertension (PAH) is a disorder in which aberrant vascular remodelling  raises pressures in the pulmonary vasculature, causing right heart failure.  Affected young adults often suffer progressive disease leading to premature death. The disease has a large genetic component, most frequently caused by mutations in the TGFβ/BMP signalling axis. However, rare subtypes such as pulmonary veno-occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH) have distinct genetic associations. There are currently no effective treatments apart from lung transplantation, and typically death occurs within a year in 72% of patients diagnosed with these aggressive PAH subtypes. 

Biallelic mutations of EIF2AK4, which encodes the kinase GCN2, are causal in these two ultra-rare subtypes of PAH. EIF2AK4 variants of unknown significance have also been identified in patients with classical PAH, though their relationship to disease remains unclear. In this new paper from the Marciniak lab, a suite of bioinformatic and experimental approaches was applied to sixteen EIF2AK4 variants that had been identified in patients.  


By testing the functional integrity of the integrated stress response (ISR) downstream of GCN2, it was determined that existing computational tools are insufficiently sensitive to reliably predict impaired kinase function. The dysfunctional variants of GCN2 that were identified could be subclassified into three groups: misfolded, kinase-dead, and hypomorphic. Intriguingly, members of the hypomorphic group were amenable to paradoxical activation by a type-1½ GCN2 kinase inhibitor. This experiment approach may aid in the clinical stratification of EIF2AK4 variants and potentially identify hypomorophic alleles receptive to pharmacological activation.