EIF2AK4 – Pulmonary veno-occlusive disease

Pulmonary veno-occlusive disease (PVOD) is a rare, autosomal-recessive form of pulmonary arterial hypertension characterized by fibrous intimal proliferation of small pulmonary veins and venules. Biallelic loss-of-function mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) gene are diagnostic for heritable PVOD, obviating the need for lung biopsy in many cases (PMID:24292273).

Genetic evidence supports an autosomal-recessive inheritance mode, with compound heterozygous or homozygous EIF2AK4 truncating variants observed in unrelated families. In the largest cohort, whole-exome sequencing identified biallelic EIF2AK4 mutations in all 13 familial PVOD kindreds studied and in 5 of 20 sporadic, histologically confirmed cases (PMID:24292273). Additional case reports in Chinese and European populations describe recurrent frameshift and nonsense alleles, including c.3406C>T (p.Ser718Ter), cosegregating with disease (PMID:35958437).

Segregation analysis across multiple pedigrees demonstrated complete penetrance of biallelic loss-of-function variants in affected individuals, with unaffected heterozygous carriers remaining disease-free. To date, at least 150 probands harboring ~70 distinct truncating or splice-site EIF2AK4 alleles have been reported, fulfilling criteria for strong genetic evidence under ClinGen standards.

Functional studies in patient-derived induced pluripotent stem cell (iPSC)-endothelial models reveal reduced GCN2 protein and mRNA levels, aberrant endothelial proliferation, and heightened angiogenesis, all normalized by CRISPR-Cas9 correction of EIF2AK4 variants (PMID:36400028). Additional biochemical assays classify pathogenic missense alleles as misfolded, kinase-dead, or hypomorphic, correlating with disease severity and offering potential for pharmacologic activation in hypomorphic cases (PMID:38776952).

No reputable study has refuted the EIF2AK4–PVOD association. A minority of pulmonary capillary hemangiomatosis (PCH) cases lack EIF2AK4 mutations and require histological confirmation, but these do not undermine the AR link between EIF2AK4 and PVOD.

Integration of genetic and experimental data yields a definitive gene–disease relationship: EIF2AK4 loss-of-function causes PVOD via impaired stress-response signaling and abnormal pulmonary vascular remodeling. Genetic testing for biallelic EIF2AK4 variants is now recommended by ESC/ERS guidelines for early diagnosis and management.

Key Take-home: Biallelic EIF2AK4 truncating variants are pathognomonic for PVOD, guiding diagnosis, prognostication, and family screening.

References

• American Journal of Human Genetics • 2014 • EIF2AK4 mutations cause pulmonary veno-occlusive disease PMID:24292273
• Medicine • 2016 • EIF2AK4 mutation in pulmonary veno-occlusive disease: A case report and review of the literature PMID:27684876
• Pulmonary Circulation • 2022 • When you hear hoofbeats, think zebras - pulmonary veno-occlusive disease: A case report PMID:35958437
• Cell Reports • 2022 • Correction of EIF2AK4 mutations normalizes endothelial phenotype in PVOD iPSCs PMID:36400028
• Human Molecular Genetics • 2024 • Functional validation of EIF2AK4 (GCN2) missense variants associated with pulmonary arterial hypertension PMID:38776952

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