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Better Understanding of Potential Genetic Mutations May Lead to Improved PAH Diagnosis, Treatment


A better understanding of the genetic etiology of pulmonary arterial hypertension and its molecular variants is needed to develop better therapies for the disease, which has no agents available that can reverse or halt it.

Pulmonary arterial hypertension (PAH) has remained a fatal disease with no pharmacological agents available to reverse or halt the disease. As there is no cure, there is an unmet need to understand the genetic etiology of PAH and molecular variants in order to develop better novel therapies.

A study published in The Application of Clinical Genetics identifies potential mutations that are responsible for PAH.

“…A number of potentially causative mutations in genes primarily related to PAH as well as genetic and epigenetic modifiers of disease expression have been discovered via advanced genetic and genomic techniques including but not limited to conventional linkage analysis and next-generation sequencing technologies,” the authors explained.

In familial cases of PAH, not all individuals at risk are affected, and women are preferentially affected in an approximate 2:1 ratio. While 6% of PAH cases are heritable PAH (HPAH), this may be an underestimate, as cases of HPAH may be misclassified as idiopathic PAH (IPAH).

In 75% of HPAH and 20% of IPAH cases, mutations in the gene encoding bone morphogenetic protein receptor type 2 (BMPR2) may be responsible. Compared with patients without the mutation, patients with PAH who have the BMPR2 mutation are not only diagnosed and die 10 years earlier, but they also are less likely to benefit from calcium channel blockers.

BMPR2 mutations are a member of the transforming growth factor-beta (TGF-β) receptor superfamily. The researchers noted that approximately 20% of families with HPAH do not have detectable mutations along this pathway.

“This has led the scientific community to search for additional mutations which may contribute to PAH pathobiology,” they explained. Other genes include:

  • KCNK3: This mutation may be a rare genetic cause of HPAH and IPAH. It is highly expressed in human pulmonary artery smooth muscle cells. Loss of its function may result in calcium-mediated vasoconstriction.
  • CAV1: This mutation is also a rare cause of HPAH and IPAH. Although the role of KCNK3 in PAH remains incomplete understood, CAV1 mutations in HPAH and IPAH have been extensively evaluated. CAV1 may modify TGF-β signaling. Observations “suggest a mechanistic link between CAV1 and BMPR2 mutations in the pathobiology of PAH.”
  • KDR and NOTCH3: These both may be involved in “cell proliferation and viability” and predispose patients to PAH.
  • NPR3: Mice lacking natriuretic peptide receptor type C, which NPR3 encodes, “exhibit echocardiographic and hemodynamic findings that are similar to those typically seen in humans with PAH.” However, the authors admit the causative genes in mice may not be relevant to humans.

Targeting molecular pathways that may contribute to PAH could provide new approaches to treat the disease. The 6th World Symposium on Pulmonary Hypertension task force recommends genetic screening even though there is no prevention or cure for PAH. However, identifying heritable disease could allow for closer monitoring, earlier disease detection, and earlier initiation of therapy.

“As genetic and other types of inherent biologic variations rarely occur in isolation, major advancements can be expected in the next few years in the identification of additional genes as well as genetic and environmental modifiers for PAH,” the authors concluded. “Larger genetic and biomarkers studies, with a close interplay of animal and human approaches will be necessary to better understand the complex genetic networks and events that promote PAH in genetically at-risk subjects.”


Eroume-A Egom E, Moyou-Somo R, Essame Oyono JL, Kamgang R. Identifying potential mutations responsible for cases of pulmonary arterial hypertension. Appl Clin Genet. 2021;14:113-124. doi:10.2147/TACG.S260755

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