A study published in the journal Nature Communications reported the case of several patients with pulmonary arterial hypertension (PAH) who carried more than one pathogenic mutation in several genes. The researchers found that these patients had more severe symptoms, which suggests that additional mutations can worsen the pathology of the disease.
The study, “Complex Inheritance In Pulmonary Arterial Hypertension Patients With Several Mutations,” was conducted by Guillermo Pousada, with the University of Vigo, Spain, and colleagues.
At both the clinical and genetic levels, PAH’s origin can be quite diverse, making it difficult to link specific gene mutations to symptoms and complicating a patient’s proper diagnosis and treatment. Most PAH patients carry mutations in the bone morphogenetic protein type 2 receptor (BMPR2) gene, but several other genes are known to contain pathogenic mutations associated with more severe symptoms at earlier ages.
Researchers compared the clinical and hemodynamic (cardiac output) parameters of patients with several mutations with patients having only one pathogenic mutation. To do so, the team analyzed several parameters in 57 unrelated PAH patients (28 patients with idiopathic PAH, and 29 with PAH associated with other health conditions, APAH).
Genetic analyses patients indicated that 15 patients carried more than one pathogenic mutation in several genes associated with PAH, such as BMPR2, ENG, ACVRL1 and KCNA5. Moreover, 12 of these patients had at least one mutation in the BMPR2 gene, supporting the role of this gene in the development of the disease.
Researchers analyzed several parameters — such as gender, age at diagnosis, mean pulmonary arterial pressure (mPaP), systolic pulmonary arterial pressure (sPaP), pulmonary vascular resistance (PVR), cardiac index (CI), 6-minute walking text (6MWT), PAH type (IPAH or APAH), and response to treatment. Compared to patients with only one mutation, those with several mutations included more women, patients who had the disease diagnosed 11 years earlier, and patients with significantly higher PVR. This group also had significant differences in CI and showed no response to therapy. There was no difference in terms of PAH type.
“As a whole, it is difficult to elucidate the role that each of the different mutations could have had in the development of disease,” the authors wrote.
Although the precise role of each mutation remains to be elucidated, the team knows that certain mutations, such as those identified in the BMPR2 gene, exert their pathogenic effect by changing the way the BMPR2 protein is produced or conserved, for instance, by generating a shorter version of the protein or a making it more susceptible to degradation. The team also noticed that several genes are linked to the same molecular pathway, so that simultaneous mutations in these genes can impair the workings of the pathway and increase the severity of the disease.
The researchers say that other genes, not included in their study, may be mutated in PAH patients as well, and their identification will provide important insights into the complexity of this disease.
“PAH is [the] consequence of a heterogeneous constellation of genetic arrangements. Patients with several pathogenic mutations seem to display a more severe phenotype,” they concluded.