Novel EIF2AK4 mutations in histologically proven pulmonary capillary hemangiomatosis and hereditary pulmonary arterial hypertension

Abstract

BackgroundPulmonary hypertension (PH) remains one of the rarest and deadliest diseases. Pulmonary Capillary Hemangiomatosis (PCH) is one of the sub-classes of PH. It was identified using histological and molecular tools and is characterized by the proliferation of capillaries into the alveolar septae. Mutations in the gene encoding the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) have recently been linked to this particular subgroup of PH.MethodsIn our effort to unveil the genetic basis of idiopathic and familial cases of PH in Lebanon, we have used whole exome sequencing to document known and/or novel mutations in genes that could explain the underlying phenotype.ResultsWe showed bi-allelic mutations in EIF2AK4 in two non-consanguineous families: a novel non-sense mutation c.1672C > T (p.Q558*) and a previously documented deletion c.560_564drlAAGAA (p.K187Rfs9*). Our histological analysis coupled with the CT-scan results showed that the two patients with the p.Q558* mutation have PH. In contrast, only one of the individuals harboring the p.K187Rfs9* variant has a documented PCH while his older brother remains asymtomatic. Differential analysis of the variants in the genes of the neighboring network of EIF2AK4 between the two siblings identified a couple of interesting missense mutations that could account for this discrepancy.ConclusionThese findings represent a novel documentation of the involvement of EIF2AK4 in the different aspects of pulmonary hypertension. The absence of a molecular mechanism that relates the abrogated function of the protein to the phenotype is still a major hurdle in our understanding of the disease.

A (dis)integrated stress response: Genetic diseases of eIF2α regulators

“…Mutations in EIF2AK4 , the gene that encodes GCN2, are associated with different forms of pulmonary hypertension including pulmonary veno‐occlusive disease, pulmonary capillary hemangiomatosis, and pulmonary arterial hypertension (Abou Hassan et al, 2019; Best et al, 2014, 2017; Eichstaedt et al, 2016; Eyries et al, 2014; Hadinnapola et al, 2017; Table 5). The primary symptoms of pulmonary hypertension are progressive exercise dyspnea, dyspnea on bending down, exercise‐induced syncope, fatigue, and edema (Hoeper et al, 2017).…”

“…The homozygous or heterozygous compound mutations identified were autosomal recessive (Best et al, 2014). More recently, mutations in EIF2AK4 have been linked to pulmonary arterial hypertension, albeit less commonly (Abou Hassan et al, 2019; Best et al, 2017; Eichstaedt et al, 2016; Hadinnapola et al, 2017). Pulmonary hypertension‐associated EIF2AK4 mutations are thought to be loss of function and likely prevent sufficient ISR activation (Figure 6a,c).…”

The integrated stress response in pulmonary disease

“…However, these mutations are variably penetrant, suggesting that additional modifying factors exist. Two subtypes of PAH, pulmonary veno-occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH) were recently shown to be caused by biallelic mutations of EIF2AK4, which encodes GCN2 (figure 3) [163][164][165]. The PVOD/PCH subtypes have an even worse prognosis than classical PAH and currently have no effective treatments apart from lung transplantation [166].…”

“…However, these mutations are variably penetrant, suggesting that additional modifying factors exist. Two subtypes of PAH, pulmonary veno-occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH) were recently shown to be caused by biallelic mutations of EIF2AK4 , which encodes GCN2 ( figure 3 ) [ 163 – 165 ].…”

SOX17 Loss-of-Function Mutation Underlying Familial Pulmonary Arterial Hypertension

“…[32][33][34][35] However, emerging evidence has demonstrated that genetic defects play a pivotal role in the pathogenesis of idiopathic PAH, especially for familial PAH, and deleterious mutations in multiple genes, including BMPR2 encoding a receptor of the transforming growth factor-β superfamily, TBX4 encoding a transcription factor, and KCNK3 as well as ABCC8 encoding potassium channels, have been found to cause PAH. 1,4,[36][37][38][39][40][41][42][43][44][45][46][47] In addition, genome-wide association studies have revealed that common genetic variations are associated with an enhanced susceptibility to PAH. 48) Nevertheless, due to substantial genetic heterogeneity of PAH, the genetic determinants underpinning PAH in the overwhelming majority of patients remain to be identified.…”