Around three-quarters of people with Primary Lymphoedema—a chronic condition where fluid builds up in tissues, causing painful swelling—never learn which faulty gene caused their disease. Without a genetic diagnosis, families cannot receive counselling, and no treatments exist beyond palliative care. The problem is that scientists know mechanical forces from fluid flow help build the lymphatic system’s valves, but they do not understand how cells sense and respond to those forces. This project will characterise a newly identified gene that appears to play a critical role in that process. By sequencing the UK’s largest cohort of Primary Lymphoedema patients, the team has already found several harmful variants in this gene. If the research succeeds, it will immediately provide clinicians with a molecular diagnosis they can share with patients and their families. In the longer term, understanding the fundamental mechanisms of lymphatic development could open the door to therapies for a disease that currently has none. This is primarily fundamental science, but with a direct and near-term clinical payoff for a patient group that has been left without answers.
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Primary Lymphoedema is a disfiguring and disabling disease characterised by defective lymphatic fluid drainage due to errors in genes that control development of the lymphatic system. Although mutations in a dozen or so genes have been linked to development of this disease, the overwhelming majority (>75%) of Primary Lymphoedema patients do not receive a genetic diagnosis, highlighting the need for identifying the genetic cause of this disease. Crucially, there are no treatments for Primary Lymphoedema, with palliative care as the patients’ only option; this is therefore a medical area of great unmet need. Accumulating evidence highlights the importance of mechanical forces in promoting proper development and function of the lymphatic system. Specifically, fluid shear stress due to lymph flow is a critical determinant of lymphatic valve development, whose malfunction can lead to lymphoedema. The mechanisms by which mechanical forces are sensed and transduced to promote lymphatic valve development are largely unknown. We now present unpublished data which identify a role for a new gene in the development and physiological function of the lymphatic system. Genetic sequencing of cohorts of Primary Lymphoedema patients identified several putative pathogenic variants in this gene, thus providing support for its crucial role in lymphatic disease. Using our unique expertise in mechanotransduction and access to the UK’s largest cohort of Primary Lymphoedema patients, we propose to comprehensively characterise the role of this gene and its associated partners in lymphatic biology and lymphoedema. This body of work will provide critically important information on the molecular and genetic mechanisms that underpin proper lymphatic development and function and identify additional genes involved in Primary Lymphoedema pathogenesis. As such, an immediate impact will be leading to a molecular report to clinicians, who can inform families and provide genetic counselling. Ultimately, our hope is that through increased understanding of the mechanisms of disease, we and others can develop therapies for these devastating diseases.
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