PAH Study Reveals Unexpected Genetic Complexity

Mutations in the ENG gene might contribute to disease mechanisms in pulmonary arterial hypertension (PAH), according to a recent study demonstrating that PAH patients often carry ENG gene changes in addition to other, more well-studied mutations. The study demonstrates that genetic contributions to PAH are more complex than anticipated, raising the need for a better understanding of molecular factors that might affect future, individualized treatment attempts.

Gene mutations increasing the risk of PAH affect a large proportion of patients, with the most commonly mutated gene, BMPR2, being deficient in 10 to 40 percent of sporadic, and 80 percent of familial PAH patients. Mutations in the ENG gene are considered much rarer.

The ENG gene encodes a receptor that is part of the TGF-β signaling pathway, and mutations are associated with hereditary hemorrhagic telangiectasia type 1, a condition characterized by blood vessel malformations. Studies have shown that ENG gene mutations can put hemorrhagic telangiectasia patients at risk for PAH.

Researchers from the University of Vigo in Spain screened 57 unrelated PAH patients for mutations in the ENG gene. The group was composed of 29 patients with idiopathic PAH, 19 patients had PAH associated with connective tissue disease, four suffered PAH related to HIV infection, and five had porto-pulmonary PAH.

Despite the notion that ENG gene mutations are rare in PAH, the study, “Mutational and clinical analysis of the ENG gene in patients with pulmonary arterial hypertension,” found 15 different mutations in 44 of the 57 patients. Using software for mutation analyses, the research team predicted that eight of the mutations were disease-causing. These mutations affected a total of 16 patients, of which seven had idiopathic PAH and nine had a disease associated with other conditions.

Data published in the journal BMC Genetics show that one particular mutation, called c.572G>A (p.G191D), was found in 10, mostly idiopathic patients. The mutation was not present in any of the 55 control individuals, and researchers observed that patients with mutations in ENG were diagnosed earlier than patients without mutations in known PAH genes.

Since all the patients carrying the c.572G>A (p.G191D) mutation also had mutations in other known PAH genes, it was difficult to conclude that any disease characteristics were linked specifically to the ENG gene.

Instead, it became obvious that the genetic background in PAH is more complex than previously believed, showing a need for more research into molecular mechanisms linked to various genetic changes, affecting disease development.