Involved group members: Miikka Vikkula, Pascal Brouillard, Nicole Revencu, Laurence Boon

Lymphedema is a strongly invalidating chronic disease resulting from abnormal development and/or function of the lymphatic system. Lymph is not drained from interstitial tissues, but accumulates, most often in lower extremities, causing enlargement, fibrosis and predisposition to secondary infections. Function of the affected body part is often compromised. In Europe, over a million people are affected. Therapy is limited to repeated manual lymphatic drainage, and use of compressive garments. In some cases, surgery may be helpful. No curative therapy exists.

Lymphedema is divided into primary (unknown cause) and secondary (known environmental cause, such as infection or surgery). Primary lymphedema is sometimes inherited from generation to generation, similar to vascular anomalies. By studying such families, we have made some major contributions. We identified the first causative gene for primary lymphedema (Milroy disease), FLT4, encoding the endothelial receptor VEGFR3, in parallel to a US group (Irrthum et al, 2000). We further demonstrated that mutations can also be recessive or even de novo, and some cause a much wider fetal lymphatic dysfunction  (hydrops fetalis), enlarging diagnostic testing indications (Ghalamkarpour et al, 2009a & 2009b). A comparative phenotypic study between mice and men, let us to discover that mutations in SOX18 cause Hypotrichosis-Lymphedema-Telangiectasia syndrome (Irrthum et al, 2003). We also showed that a premature stop codon in this gene induces an associated glomerulonephritis, which necessitates renal transplantation (Moalem et al, 2014). We contributed to the discovery of CCBE1 as being mutated in generalized lymphatic dysplasia (the Hennekam syndrome) (Alders et al, 2009), and KIF11 in Microcephaly with or without Chorioretinopathy, Lymphedema, or Mental retardation syndrome (Ostergaard et al, 2012; Schlögel et al, 2015). Recently we discovered that recessive loss-of-function mutations in ADAMTS3 cause Hennekam Lymphangiectasia-Lymphedema syndrome 3 (Brouillard et al, 2017). Another variant in ADAMTS3 disrupts its proper localization at the cell surface, displacing its specific catalytic action towards VEGFC, the VEGFR3 ligant (Jha et al, 2017). Lately we unravelled two novel mutations in VEGFC that alter mRNA splicing, abolishing its function (Fastré et al, under revision).

To date, at least 28 genes are known to cause primary lymphedema and no curative therapy exists (Brouillard et al, 2014; Brouillard et al, 2017).  These genes explain the disease in barely 30% of the patients.

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