Functional characterisation of causative genes for human primary lymphoedema

Recently gained insights into mechanisms of lymphangiogenesis have been driven by the characterisation of animal models with specific lymphatic defects, and identification of genes causative of human primary lymphoedemas. In collaboration with Pia Ostergaard, Sahar Masour, Steve Jeffery, Peter Mortimer and their teams at St George’s Hospital in London, we have recently identified GATA2 and KIF11 as two novel causative genes for primary lymphoedema by whole-exome sequencing. We are currently investigating the biological function of GATA2 and KIF11 in lymphatic development by combining state-of-the-art mouse genetics with in vitro studies on primary lymphatic endothelial cells. The results from this project are expected to increase our understanding of normal lymphatic development and pathophysiological mechanisms involved in lymphoedema and other lymphatic disorders.


Ostergaard et al. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet. 2012;90(2):356-62. PubMed

Ostergaard et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Gen 2011;43:929-923. PubMed

Martin-Almedina S*, Martinez-Corral I*, et al. Kinase inactivating mutations in EPHB4 cause autosomal dominant lymphatic-related hydrops fetalis. J Clin Invest 2016;26:3080-8. PubMed

Frye M, Taddei A, Dierkes C, Martinez-Corral I, Fielden M, Ortsäter H, Kazenwadel J, Calado DP, Ostergaard P, Salminen M, He L, Harvey N, Kiefer F, Mäkinen T. Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program. Nat Commun 9:1511 (2018) doi: 10.1038/s41467-018-03959-6. PubMed