RESUMO
Recent whole exome sequencing studies in humans have provided novel insight into the importance of the ephrinB2-EphB4-RASA1 signaling axis in cerebrovascular development, corroborating and extending previous work in model systems. Here, we aim to review the human cerebrovascular phenotypes associated with ephrinB2-EphB4-RASA1 mutations, including those recently discovered in Vein of Galen malformation: the most common and severe brain arteriovenous malformation in neonates. We will also discuss emerging paradigms of the molecular and cellular pathophysiology of disease-causing ephrinB2-EphB4-RASA1 mutations, including the potential role of somatic mosaicism. These observations have potential diagnostic and therapeutic implications for patients with rare congenital cerebrovascular diseases and their families.
Assuntos
Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/metabolismo , Efrina-B2/metabolismo , Neovascularização Fisiológica , Receptor EphB4/metabolismo , Transdução de Sinais , Proteína p120 Ativadora de GTPase/metabolismo , Animais , Transtornos Cerebrovasculares/patologia , Suscetibilidade a Doenças , Efrina-B2/química , Efrina-B2/genética , Predisposição Genética para Doença , Humanos , Receptor EphB4/química , Receptor EphB4/genética , Relação Estrutura-Atividade , Proteína p120 Ativadora de GTPase/química , Proteína p120 Ativadora de GTPase/genéticaRESUMO
Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for â¼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.