As TM has anti-coagulant, anti-inflammatory, and cytoprotective properties and also attenuates alternative complement activation, this glycoprotein could play an active role in other diseases with endothelial involvement apart from aHUS.
Four missense mutations, CFH p.V837I, p.Y1058H, p.V1060L and THBDp.R403K may predispose to aHUS manifestation; the remaining seven missense mutations were likely neutral.
Mutations in proteins that regulate complement (factor H, factor I, MCP/CD46, thrombomodulin) or promote (C3, factor B) amplification of its alternative pathway or anti-factor H antibodies predispose to aHUS.
Mutations in complement factor H (CFH), factor I (CFI), factor B (CFB), thrombomodulin (THBD), C3 and membrane cofactor protein (MCP), and autoantibodies against factor H (αFH) with or without a homozygous deletion in CFH-related protein 1 and 3 (∆CFHR1/3) predispose development of atypical hemolytic uremic syndrome (aHUS).
We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic-uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells.