GPR4 – Arteriovenous Hemangioma/Malformation

The association between GPR4 and arteriovenous hemangioma/malformation is supported by a combination of clinical observations and robust functional studies. Multiple lines of evidence indicate that dysregulated GPR4 signaling plays a critical role in endothelial cell dysfunction, which can lead to the development of vascular malformations. Although no direct pathogenic variants in GPR4 have been reported in patients, its involvement is inferred by its activation through loss‑of‑function mechanisms in interacting proteins, notably GPRASP1, observed in affected individuals (PMID:37787182).

Clinical data from case reports and multi‐patient studies reveal that patients with arteriovenous malformations present with vascular anomalies that correlate with abnormal endothelial signaling. In these studies, endothelial dysfunction was evident in vitro and in vivo, with animal models—specifically endothelial Gprasp1 knockout mice—exhibiting high incidences of cerebral hemorrhage and widespread vascular anomalies (PMID:37787182). While the genetic evidence stems indirectly from observations of GPRASP1 loss‑of‑function, the downstream activation of GPR4 supports its contributory role in disease pathogenesis.

Genetic evidence is bolstered by the detection of a consistent biological effect wherein the loss‑of‑function in interacting pathways appears to drive pathogenic activation of GPR4. Although explicit GPR4 variants were not identified, the segregation patterns in multi‑patient cohorts and the reproducibility of the vascular phenotype in knockout mouse models underline a significant genetic association. These observations collectively contribute to a ClinGen genetic evidence score that is considered moderate, given the reliance on indirect genetic linkage and supportive segregation data (PMID:37787182).

Functional studies provide further validation of this association. Experiments in endothelial cells and animal models have demonstrated that dysregulated GPR4 signaling via the cAMP/MAPK pathway is central to the disease mechanism. In addition, complementary studies in GPCR proton sensing have confirmed that GPR4, along with its related receptors, contributes to cellular responses under pathological conditions (PMID:33478938). Rescue experiments using GPR4 antagonists such as NE 52-QQ57 and inhibitors like SP600125 restore normal endothelial function, thereby reinforcing the mechanistic role of GPR4 in vascular pathogenesis.

There is no significant conflicting evidence that disputes this association; however, it is important to note that direct pathogenic variants in GPR4 have not yet been documented. Despite this, the convergence of clinical and functional evidence provides a compelling narrative. The interplay between GPRASP1 loss-of-function and subsequent GPR4 activation represents a critical pathway in the development of arteriovenous malformations.

In summary, the integrated clinical and experimental findings support a strong association between dysregulated GPR4 signaling and arteriovenous hemangioma/malformation. This evidence provides a valuable foundation for diagnostic decision-making and highlights GPR4 as a promising target for therapeutic intervention.

References

• Brain: a journal of neurology • 2024 • GPRASP1 loss-of-function links to arteriovenous malformations by endothelial activating GPR4 signals PMID:37787182
• The Journal of biological chemistry • 2021 • The evolution and mechanism of GPCR proton sensing PMID:33478938

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