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.
- Fastre E, Brouillard P, Lanteigne L-E, et al. Splice-site mutations in VEGFC cause loss-of-function and Nonne-Milroy-like primary lymphedema. Clin. Genet. under revision.
- Jha SK, Rauniyar K, Karpanen T, et al. Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1. Sci Rep. 2017;7(1):4916.
- Brouillard P, Dupont L, Helaers R, et al. Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3. Hum. Mol. Genet. 2017;26(21):4095-4104.
- Schlögel MJ, Mendola A, Fastré E, Vasudevan P, Devriendt K, de Ravel TJ, Van Esch H, Casteels I, Arroyo Carrera I, Cristofoli F, Fieggen K, Jones K, Lipson M, Balikova I, Singer A, Soller M, Mercedes Villanueva M, Revencu N, Boon LM, Brouillard P, Vikkula M. No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome. Orphanet J Rare Dis. 2015 May 2;10:52.
- Alders M, Hogan BM, Gjini E, Salehi F, Al-Gazali L, Hennekam EA, Holmberg EE, Mannens MM, Mulder MF, Offerhaus GJ, Prescott TE, Schroor EJ, Verheij JB,Witte M, Zwijnenburg PJ, Vikkula M, Schulte-Merker S, Hennekam RC. Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat. Genet. 2009; 41(12):1272-1274.
- Brouillard P, Boon L, Vikkula M. Genetics of lymphatic anomalies. J. Clin. Invest. 2014; 124(3):898-904.
- Ghalamkarpour A, Holnthoner W, Saharinen P, Boon LM, Mulliken JB, Alitalo K, Vikkula M. Recessive primary congenital lymphoedema caused by a VEGFR3 mutation. J. Med. Genet. 2009; 46(6):399-404.
- Ghalamkarpour A, Debauche C, Haan E, Van Regemorter N, Sznajer Y, Thomas D, Revencu N, Gillerot Y, Boon LM, Vikkula M. Sporadic in utero generalized edema caused by mutations in the lymphangiogenic genes VEGFR3 and FOXC2. J. Pediatr. 2009; Jul;155(1):90-3.
- Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am. J. Hum. Genet. 2000; Aug;67(2):295-301.
- Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensel MA, Vikkula M. Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am. J. Hum. Genet. 2003; 72(6):1470-8.
- Moalem S, Brouillard P, Kuypers D, Legius E, Harvey E, Taylor G, Francois M, Vikkula M, Chitayat D. Hypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene. Clin. Genet. 2014; 87(4):378-82.
- Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, van Impel A, Moore AT, Loeys BL, Ghalamkarpour A, Onoufriadis A, Martinez-Corral I,Devery S, Leroy JG, van Laer L, Singer A, Bialer MG, McEntagart M, Quarrell O, Brice G, Trembath RC, Schulte-Merker S, Makinen T, Vikkula M, Mortimer PS,Mansour S, Jeffery S. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am. J. Hum. Genet. 2012; 90(2):356-62.