ArticleHuman molecular genetics2018
Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 99 citations in OpenAlex.
- SHOC2 Is a Novel Cause of Central Conducting Lymphatic Anomaly.American journal of medical genetics. Part A · 2026Article
- Capillary Malformation-Arteriovenous Malformation Syndrome Associated with RASA1 and EPHB4 Mutations: Comparative Case Series and Narrative Review.Life (Basel, Switzerland) · 2026Review
- Multidimensional single-cell analysis reveals immune dysfunction and inflammatory response in lymphatic malformations.Protein & cell · 2026Article
- Insights Into Congenital Lymphatic Anomalies Underlying Fetal Effusions.Prenatal diagnosis · 2026Article
- Effects of MEK-inhibitor treatment in infants with lymphatic abnormalities in noonan syndrome.Frontiers in pediatrics · 2026Article
- Expansion of the Phenotype of Lymphatic Anomalies Caused by Somatic Activating BRAF Variant.Pediatric blood & cancer · 2025Article
- Zebrafish Models of Induced Lymphangiogenesis: Current Advancements and Therapeutic Discovery.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Lymphatic malformations involving the thorax in children: a retrospective cohort study.BMC pulmonary medicine · 2025Article
- Molecular landscape and classification of vascular anomalies.Hematology. American Society of Hematology. Education Program · 2024Review
- Implementing genomic medicine in clinical practice for adults with undiagnosed rare diseases.NPJ genomic medicine · 2024Article
- EPHB4-RASA1 Inhibition of PIEZO1 Ras Activation Drives Lymphatic Valvulogenesis.Circulation research · 2024Article
- The utility of dynamic contrast-enhanced intranodal magnetic resonance lymphangiography (MRL) in the investigation of primary lymphatic anomalies.Clinical radiology · 2024Article
- Central conducting lymphatic anomaly: from bench to bedside.The Journal of clinical investigation · 2024Review
- Lymphatic vessel: origin, heterogeneity, biological functions, and therapeutic targets.Signal transduction and targeted therapy · 2024Review
- Review
- An EPHB4-RASA1 signaling complex inhibits shear stress-induced Ras-MAPK activation in lymphatic endothelial cells to promote the development of lymphatic vessel valves.bioRxiv : the preprint server for biology · 2023Article
- Temporospatial inhibition of Erk signaling is required for lymphatic valve formation.Signal transduction and targeted therapy · 2023Article
- Pathological angiogenesis: mechanisms and therapeutic strategies.Angiogenesis · 2023Review
- Genomic profiling informs diagnoses and treatment in vascular anomalies.Nature medicine · 2023Article
- Pathogenic variants in PIK3CA are associated with clinical phenotypes of kaposiform lymphangiomatosis, generalized lymphatic anomaly, and central conducting lymphatic anomaly.Pediatric blood & cancer · 2023Article
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Authors and funding
24 authors at 4 institutions in 2 countries.
Funding
Abstract
Central conducting lymphatic anomaly (CCLA) is one of the complex lymphatic anomalies characterized by dilated lymphatic channels, lymphatic channel dysmotility and distal obstruction affecting lymphatic drainage. We performed whole exome sequencing (WES) of DNA from a four-generation pedigree and examined the consequences of the variant by transfection of mammalian cells and morpholino and rescue studies in zebrafish. WES revealed a heterozygous mutation in EPHB4 (RefSeq NM_004444.4; c.2334 + 1G>C) and RNA-Seq demonstrated that the EPHB4 mutation destroys the normal donor site, which leads to the use of a cryptic splice donor that results in retention of the intervening 12-bp intron sequence. Transient co-expression of the wild-type and mutant EPHB4 proteins showed reduced phosphorylation of tyrosine, consistent with a loss-of-function effect. Zebrafish ephb4a morpholino resulted in vessel misbranching and deformities in the lymphatic vessel development, indicative of possible differentiation defects in lymphatic vessels, mimicking the lymphatic presentations of the patients. Immunoblot analysis using zebrafish lysates demonstrated over-activation of mTORC1 as a consequence of reduced EPHB4 signaling. Strikingly, drugs that inhibit mTOR signaling or RAS-MAPK signaling effectively rescued the misbranching phenotype in a comparable manner. Moreover, knock-in of EPHB4 mutation in HEK293T cells also induced mTORC1 activity. Our data demonstrate the pathogenicity of the identified EPHB4 mutation as a novel cause of CCLA and suggesting that ERK inhibitors may have therapeutic benefits in such patients with complex lymphatic anomalies.
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