CAV1 – Heritable Pulmonary Arterial Hypertension

Heritable pulmonary arterial hypertension (HPAH) is a rare, autosomal dominant disorder characterized by progressive remodeling of small pulmonary arterioles, leading to elevated pulmonary artery pressure, right ventricular failure, and high mortality. While mutations in BMPR2 account for the majority of HPAH, mutations in the caveolin-1 gene (CAV1) have emerged as a monogenic cause in a subset of families. The identification of CAV1 variants informs genetic testing panels and guides family screening and management for patients with HPAH (MONDO:0017148).

Genetic Evidence

Autosomal dominant inheritance of HPAH due to CAV1 was first demonstrated by segregation of a heterozygous frameshift variant, c.474del (p.Leu159SerfsTer22), in a multigenerational family with clinically confirmed pulmonary hypertension (PMID:28468941). This variant truncates the C-terminal tail of caveolin-1, and segregates with disease in all affected relatives (n=2) in the kindred, with no unaffected carriers. No additional unrelated probands have been reported to date.

Functional and Experimental Evidence

In patient-derived fibroblasts, the c.474del mutation causes retention of mutant caveolin-1 in the endoplasmic reticulum, a two-fold increase in cell proliferation, and hyperphosphorylation of Smad1/5/8, indicating loss of the protein’s antiproliferative function (PMID:28468941). A knock-in mouse model expressing the human CAV1 frameshift mutation recapitulates key features of PAH, including elevated right ventricular pressure, right ventricular hypertrophy, and pulmonary vascular remodeling, further supporting a haploinsufficiency mechanism (PMID:33015095).

Mechanism of Pathogenicity and Clinical Integration

The truncated caveolin-1 protein disrupts caveolae assembly and fails to suppress Smad1/5/8 signaling, leading to fibroblast hyperproliferation and vascular remodeling. These data converge on a haploinsufficiency mechanism whereby loss of caveolin-1’s regulatory role in TGF-β/BMP pathways contributes to pulmonary arteriole occlusion. Genetic testing for CAV1 should be considered in HPAH patients lacking BMPR2 mutations, particularly when family history suggests an autosomal dominant pattern. Identification of CAV1 variants enables early intervention and familial cascade screening.

Key Take-home: CAV1 heterozygous frameshift mutations cause autosomal dominant HPAH via loss of caveolin-1 antiproliferative function, supporting inclusion of CAV1 in genetic testing panels.

References

• Molecular Biology of the Cell • 2017 • Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension PMID:28468941
• Frontiers in Medicine • 2020 • Expression of a Human Caveolin-1 Mutation in Mice Drives Inflammatory and Metabolic Defect-Associated Pulmonary Arterial Hypertension PMID:33015095

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