CAV1 – Pulmonary Arterial Hypertension

Autosomal dominant variants in CAV1 have been identified as a rare cause of pulmonary arterial hypertension. Initial exome sequencing in a three-generation family revealed a heterozygous frameshift in CAV1 segregating with PAH, followed by an independent de novo frameshift in a child with idiopathic PAH ([PMID:22474227]). A separate patient presenting with both PAH and congenital generalized lipodystrophy harbored a heterozygous Phe160Ter mutation in CAV1 ([PMID:27717241]).

Segregation analysis demonstrated co-segregation of loss-of-function CAV1 alleles with disease in at least four affected relatives across a multigenerational pedigree. To date, three unrelated probands with heterozygous CAV1 frameshift or nonsense variants (LoF) have been reported, consistent with autosomal dominant inheritance and reduced penetrance.

The variant spectrum in PAH is dominated by loss-of-function alleles, including c.473del (p.Pro158SerfsTer?) and c.474del (p.Leu159SerfsTer22) frameshifts and p.Phe160Ter nonsense. No recurrent missense variants have been linked to PAH to date. One representative allele, c.474del (p.Leu159SerfsTer22), has been functionally characterized.

Patient‐derived fibroblasts carrying CAV1 LoF mutations form morphologically typical caveolae but exhibit reduced stability of oligomeric CAV1 complexes, impaired cavin-1 colocalization, and hyperphosphorylation of Smad1/5/8, leading to increased fibroblast proliferation ([PMID:28468941]). Reconstitution in Cav1–/– mouse embryonic fibroblasts recapitulated these defects.

A knock-in mouse model expressing the human CAV1 C-terminal truncating mutation showed low mutant protein stability, mild pulmonary hypertension, metabolic disturbances, and an inflammatory phenotype mirroring patient features, further supporting a pathogenic role for CAV1 LoF in PAH ([PMID:33015095]).

The concordance of genetic segregation, multiple unrelated probands with heterozygous LoF CAV1 alleles, and consistent cellular and animal model phenotypes establish a definitive gene–disease relationship. Genetic testing for CAV1 should be considered in PAH patients, particularly when common TGF-β pathway mutations are absent.

Key take-home: CAV1 LoF variants cause autosomal dominant PAH through defective caveolae dynamics and dysregulated Smad signaling, supporting their inclusion in diagnostic gene panels.

References

• Circulation: Cardiovascular Genetics • 2012 • Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. PMID:22474227
• Traffic (Copenhagen, Denmark) • 2016 • Characterization of a caveolin-1 mutation associated with both pulmonary arterial hypertension and congenital generalized lipodystrophy. PMID:27717241
• 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
• Genetics in Medicine • 2023 • Defining the clinical validity of genes reported to cause pulmonary arterial hypertension. PMID:37422716

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