Pulmonary capillary hemangiomatosis: a focus on the EIF2AK4 mutation in onset and pathogenesis

Abstract

Pulmonary capillary hemangiomatosis (PCH) is a pulmonary vascular disease that mainly affects small capillaries in the lung, and is often misdiagnosed as pulmonary arterial hypertension or pulmonary veno-occlusive disease due to similarities in their clinical presentations, prognosis, and management. In patients who are symptomatic, there is a high mortality rate with median survival of 3 years after diagnosis. Both idiopathic and familial PCH cases are being reported, indicating there is genetic component in disease etiology. Mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene were identified in familial and idiopathic PCH cases, suggesting EIF2AK4 is a genetic risk factor for PCH. EIF2AK4 mutations were identified in 100% (6/6) of autosomal recessively inherited familial PCH and 20% (2/10) of sporadic PCH cases. EIF2AK4 is a member of serine/threonine kinases. It downregulates protein synthesis in response to a variety of cellular stress such as hypoxia, viral infection, and amino acid deprivation. Bone morphogenetic protein receptor 2 (BMPR2) is a major genetic risk factor in pulmonary arterial hypertension and EIF2AK4 potentially connects with BMPR2 to cause PCH. L-Arginine is substrate of nitric oxide synthase, and L-arginine is depleted during the production of nitric oxide, which may activate EIF2AK4 to inhibit protein synthesis and negatively regulate vasculogenesis. Mammalian target of rapamycin and EIF2α kinase are two major pathways for translational regulation. Mutant EIF2AK4 could promote proliferation of small pulmonary arteries by crosstalk with mammalian targets of the rapamycin signaling pathway. EIF2AK4 may regulate angiogenesis by modulating the immune system in PCH pathogenesis. The mechanisms of abnormal capillary angiogenesis are suggested to be similar to that of tumor vascularization. Specific therapies were developed according to pathogenesis and are proved to be effective in reported cases. Targeting the EIF2AK4 pathway may provide a novel therapy for PCH.

Vasoproliferative process resembling pulmonary capillary hemangiomatosis in a cat

“…However, there was no evidence of PVOD in this cat. In humans, mutations in the EIF2AK4 gene are a risk factor in the development of PCH [ 14 ]. Future studies investigating the aforementioned EIF2AK4 gene mutation are needed to establish this association in dogs and cats with PCH.…”

“…In humans, PCH has been described in association with aortic stenosis [ 6 ], Kartagener syndrome [ 7 ], systemic lupus erythematous [ 8 ], scleroderma [ 9 ], Takayasu’s arteritis [ 10 ], hypertrophic cardiomyopathy [ 11 ] and neoplasia [ 12 , 13 ]. Mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) gene are a risk factor in the development of PCH [ 14 ]. It has also been proposed that PCH is not a separate disease, but rather represents a secondary angioproliferative response to pulmonary venous hypertension as seen in PVOD [ 4 ].…”

Establishment and verification of a prognostic model of liver cancer by RNA-binding proteins based on the TCGA database

“…EIF2AK4 gene mutation has been confirmed in pulmonary vein occlusive disease (PVOD) and pulmonary capillary hemangioma (PCH) (45,46), but there are no relevant studies confirming its pathogenesis and prognostic roles in liver cancer. Huang et al (47) also confirmed through similar studies that CNOT6, UPF3B, MRPL54, IFIT5 and PPARGC1A are the key RBP coding genes for primary HCC and can also predict the survival of patients.…”

Genetics and clinics: current applications, limitations, and future developments

“…Pulmonary veno-occlusive hypertension is allelic at the PPH1 locus ( BMPR2 ), while the recessive form is caused by mutations in EIF2AK4. 42 Finally, Group 5 PH includes a variety of acquired and heritable diseases such as the AD lymphangioleiomyomatosis 43 and lysosomal storage diseases such as glycogen storage disease types 1 and 3 44 , 45 and Gaucher disease type 1 46 , 47 . Clinical genetics with counselling and pedigree construction, search for known risk factors and annotation of novel potential risk factors, family investigation, and genetic testing are currently being translated in the clinical setting.…”