Loss of ADAMTS3 activity causes Hennekam lymphangiectasia–lymphedema syndrome 3

Abstract

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.

Genetic tests in lymphatic vascular malformations and lymphedema

“…In 2014, the same authors identified homozygous or compound heterozygous mutations in FAT4 in patients diagnosed with HKLLS 21. Finally, Brouillard and coworkers recently found that loss-of-function mutations in ADAMTS3 are associated with the onset of a form of HKLLS, which they defined as HKLLS3 22. Its features are very similar to those of HKLLS1 and 2.…”

Splice‐site mutations in VEGFC cause loss of function and Nonne‐Milroy‐like primary lymphedema

“…Primary lymphedema (PLE) is phenotypically heterogeneous and partially explained by mutations in 28 genes. 1,2 In Nonne-Milroy disease (OMIM 153100), PLE appears typically at birth and is autosomal dominant with incomplete penetrance. Several mutations have been discovered in VEGFR3, but only 2 in its ligand VEGFC (c.571_572insTT; p.Pro191Leufs*10 and c.628C>T; p.Arg210*; Figure 1G), causing Milroy-like disease (OMIM 615907).…”

CHAPLE syndrome uncovers the primary role of complement in a familial form of Waldmann's disease

“…30,31 The symptoms of the patients were reminiscent of those of Hennekam syndrome 1, caused by CCBE1 mutation. 31,32 Recent studies have demonstrated that CCBE1 and ADAMTS3 play important roles in lymphatic development. Lymphatic endothelial cell proliferation and migration is driven by a tyrosine kinase receptor, vascular endothelial growth factor receptor-3 (VEGFR-3).…”