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Hum Mol Genet. 2017 Nov 1;26(21):4095-4104. doi: 10.1093/hmg/ddx297.

Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3.

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Human Molecular Genetics, de Duve Institute, University of Louvain, 1200 Brussels, Belgium.
Laboratory of Connective Tissues Biology, University of Liège, 4000 Liège, Belgium.
Pediatric Medical Genetics, Vanderbilt University Medical Center, Nashville 37232, TN, USA.
East Tennessee Children's Hospital, University of Tennessee Medical Center, Knoxville, TN 37916, USA.
Walloon Excellence in Life Sciences and Biotechnology (WELBIO), de Duve Institute, University of Louvain, 1200 Brussels, Belgium.


Primary lymphedema is due to developmental and/or functional defects in the lymphatic system. It may affect any part of the body, with predominance for the lower extremities. Twenty-seven genes have already been linked to primary lymphedema, either isolated, or as part of a syndrome. The proteins that they encode are involved in VEGFR3 receptor signaling. They account for about one third of all primary lymphedema cases, underscoring the existence of additional genetic factors. We used whole-exome sequencing to investigate the underlying cause in a non-consanguineous family with two children affected by lymphedema, lymphangiectasia and distinct facial features. We discovered bi-allelic missense mutations in ADAMTS3. Both were predicted to be highly damaging. These amino acid substitutions affect well-conserved residues in the prodomain and in the peptidase domain of ADAMTS3. In vitro, the mutant proteins were abnormally processed and sequestered within cells, which abolished proteolytic activation of pro-VEGFC. VEGFC processing is also affected by CCBE1 mutations that cause the Hennekam lymphangiectasia-lymphedema syndrome syndrome type1. Our data identifies ADAMTS3 as a novel gene that can be mutated in individuals affected by the Hennekam syndrome. These patients have distinctive facial features similar to those with mutations in CCBE1. Our results corroborate the recent in vitro and murine data that suggest a close functional interaction between ADAMTS3 and CCBE1 in triggering VEGFR3 signaling, a cornerstone for the differentiation and function of lymphatic endothelial cells.

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