What causes limbs to swell?
Primary lymphoedema is a group of disorders that are predominantly associated with swelling of a limb.
This is caused by a build-up of fluid and is due to a problem with the lymphatic system.
This system is important for immunity and for transporting lymph (similar to the liquid component of blood) from the tissues to the blood.
In recent years, the identification of additional symptoms has led to the development of a classification system for primary lymphoedema.
This divides primary lymphoedema into a variety of syndromes, each of which have a unique combination of symptoms and a distinct genetic basis.
One of these syndromes, lymphatic-related (non-immune) hydrops fetalis (LRHF) is a general swelling of the fetus, which can be fatal.
In this paper, the role of mutations in the gene for EPHB4, a protein involved in signalling processes during development was investigated.
Biochemical analysis showed that specific mutations of EPHB4 in patients prevented phosphorylation (chemical modification) at these sites,
which in turn prevented EPHB4 from passing the signal on.
Without the phosphorylated sites, the signalling pathway is broken and development of the lymphatic system cannot proceed as normal.
Furthermore, complete removal of the gene for EPHB4 has been linked to faulty lymphatic valve development.
Therefore, the valves can no longer ensure the lymph flows one-way round the lymphatic system.
This highlights the importance of EPHB4 in the early developmental stages of the lymphatic system.
The lymphatic system has many beneficial roles but in primary lymphoedema it can be a source of problems.
Learning about the effect of mutations associated with primary lymphoedema is vital for informing future development of therapies.
View the paper