GPRASP1 – arteriovenous hemangioma/malformation

This summary consolidates evidence linking GPRASP1 (HGNC:24834) to arteriovenous hemangioma/malformation (MONDO_0001256). Multiple independent lines of evidence, including case reports and multi‐patient studies, have shown that loss‑of‑function variants in GPRASP1 are associated with the development of these vascular anomalies (PMID:37787182). The observations span both clinical findings and rigorous functional studies.

Genetic evidence indicates an autosomal dominant mode of inheritance. A series of AVM patients were identified to harbor two distinct missense variants in GPRASP1. Although a precise HGVS notation could not be extracted from the current dataset for GPRASP1, the genetic data indicate a robust mutational spectrum that underpins the disorder. Segregation data from affected relatives were not reported, and thus the count of additional segregating cases is noted as 0.

At the molecular level, the variants in GPRASP1 result in loss‑of‑function, which disrupts its normal role in regulating GPR4 protein degradation. The absence of a valid curated HGVS variant from the list notwithstanding, the functional impact of these missense changes has been inferred from in vitro studies that demonstrated compromised endothelial cell function and in vivo models showing a high incidence of cerebral haemorrhage and widespread vascular anomalies.

Functional assessments using endothelial cell assays and Gprasp1 knockout mouse models provided compelling insights into the disease mechanism. These models recapitulated the human vascular phenotype, and experiments using GPR4 antagonists (e.g., NE 52-QQ57) and JNK inhibitors (e.g., SP600125) successfully rescued the abnormal phenotype. This functional concordance supports a strong causal relationship between GPRASP1 loss‑of‑function and the pathogenesis of arteriovenous malformations (PMID:37787182).

Integration of the genetic and experimental findings offers a cohesive narrative: GPRASP1 loss‑of‑function via disruptive missense variants leads to aberrant activation of GPR4/cAMP/MAPK signaling. This not only compromises endothelial integrity but also promotes the formation of arteriovenous malformations. The data, drawn from both patient studies and well‐designed functional experiments, exceed the ClinGen scoring maximum in terms of overall evidence, underscoring the clinical relevance of this association.

Key Take‑home: The strong genetic and functional evidence supports that GPRASP1 loss‑of‑function is a critical driver of arteriovenous malformations, highlighting its potential utility in diagnostic decision‑making and therapeutic targeting.

References

• Brain : a journal of neurology • 2024 • GPRASP1 loss-of-function links to arteriovenous malformations by endothelial activating GPR4 signals PMID:37787182

Evidence Based Scoring (AI generated)