Background and Objective: Blue rubber bleb nevus syndrome (BRBN) or Bean syndrome is a
rare Venous Malformation (VM)-associated disorder, which mostly affects the skin and gastrointestinal
tract in early childhood. Somatic mutations in TEK have been identified from BRBN patients; however, the
etiology of TEK mutation-negative patients of BRBN need further investigation.
Methods: Two unrelated sporadic BRBNs and one sporadic VM were firstly screened for any rare nonsilent
mutation in TEK by Sanger sequencing and subsequently applied to whole-exome sequencing to
identify underlying disease causative variants. Overexpression assay and immunoblotting were used to
evaluate the functional effect of the candidate disease causative variants.
Results: In the VM case, we identified the known causative somatic mutation in the TEK gene c.2740C>T
(p.Leu914Phe). In the BRBN patients, we identified two rare germline variants in GLMN gene c.761C>G
(p.Pro254Arg) and c.1630G>T(p.Glu544*). The GLMN-P254R-expressing and GLMN-E544X-expressing
HUVECs exhibited increased phosphorylation of mTOR-Ser-2448 in comparison with GLMN-WTexpressing
HUVECs in vitro.
Conclusion: Our results demonstrated that rare germline variants in GLMN might contribute to the
pathogenesis of BRBN. Moreover, abnormal mTOR signaling might be the pathogenesis mechanism
underlying the dysfunction of GLMN protein.