ArticleJCI insight2021
KRAS-driven model of Gorham-Stout disease effectively treated with trametinib.
Article in JCI insight, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers, 1 of them a synthesis that pooled it.
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Who cites it
57 citing papers in PubMed, 1 synthesis or guideline pooled it, 76 citations in OpenAlex.
- Clinical features and current management experience in Gorham-Stout disease: a systematic review.Orphanet journal of rare diseases · 2025Pooled it
- Vascular-lymphatic dual circulation in bone health and disease: Mechanistic coupling and translational therapeutics.Journal of orthopaedic translation · 2026Review
- RAS-PI3Kα signaling regulates KrasG12D-induced lymphangiogenesis in complex lymphatic anomalies.Disease models & mechanisms · 2026Article
- Therapeutic Efficacy of Sirolimus in Skeletal Manifestations of Gorham-Stout Disease in Adults: A Systematic Review.Cureus · 2026Review
- VEGF-D-induced intraosseous lymphangiogenesis drives site-specific heterotopic bone resorption.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Lymphatic Malformations With Activating KRAS Mutations Impair Lymphatic Valve Development Through Matrix Metalloproteinases.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- MEK Inhibition Reduces Vascular Malformations and Gene Dysregulation in NRASPediatric blood & cancer · 2026Article
- Targeting lymphatic vessels enhances bone regeneration by augmenting osteoclast activity in mouse models of amputation.The Journal of clinical investigation · 2026Article
- The role of the lymphatic system in musculoskeletal system health and disease: research progress and future directions.Bone research · 2026Review
- Vascular malformations: from genetics to therapeutics.EMBO molecular medicine · 2026Review
- Clavicular Gorham-Stout disease: a rare case report and literature review.Frontiers in endocrinology · 2026Review
- Trp53 loss drives the neoplastic transformation of Pik3caH1047R-induced vascular malformation in a mouse model.PloS one · 2026Article
- Identification of lymphatic vessels in skull periosteum but not bone marrow reveals skull channel heterogeneity.The Journal of experimental medicine · 2025Article
- Phloridzin Mitigates Gorham-Stout Disease by Dual Inhibition of Osteoclastogenesis Related to the CaACS omega · 2025Article
- Zebrafish Models of Induced Lymphangiogenesis: Current Advancements and Therapeutic Discovery.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Targeted Therapy for Complex Lymphatic Anomalies in Patients with Noonan Syndrome and Related Disorders.International journal of molecular sciences · 2025Article
- Targeted Therapies for Slow-Flow Vascular Malformations.The Australasian journal of dermatology · 2025Review
- RAS Pathway Mutations and Therapeutics in Vascular Anomalies.Pediatric blood & cancer · 2025Review
- A single-cell atlas of normal and KRASG12D-malformed lymphatic vessels.JCI insight · 2025Article
- Exploring the genetic alterations of Gorham-Stout disease.Frontiers in endocrinology · 2025Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
Gorham-Stout disease (GSD) is a sporadically occurring lymphatic disorder. Patients with GSD develop ectopic lymphatics in bone, gradually lose bone, and can have life-threatening complications, such as chylothorax. The etiology of GSD is poorly understood, and current treatments for this disease are inadequate for most patients. To explore the pathogenesis of GSD, we performed targeted high-throughput sequencing with samples from a patient with GSD and identified an activating somatic mutation in KRAS (p.G12V). To characterize the effect of hyperactive KRAS signaling on lymphatic development, we expressed an active form of KRAS (p.G12D) in murine lymphatics (iLECKras mice). We found that iLECKras mice developed lymphatics in bone, which is a hallmark of GSD. We also found that lymphatic valve development and maintenance was altered in iLECKras mice. Because most iLECKras mice developed chylothorax and died before they had significant bone disease, we analyzed the effect of trametinib (an FDA-approved MEK1/2 inhibitor) on lymphatic valve regression in iLECKras mice. Notably, we found that trametinib suppressed this phenotype in iLECKras mice. Together, our results demonstrate that somatic activating mutations in KRAS can be associated with GSD and reveal that hyperactive KRAS signaling stimulates the formation of lymphatics in bone and impairs the development of lymphatic valves. These findings provide insight into the pathogenesis of GSD and suggest that trametinib could be an effective treatment for GSD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.