The predicted structural consequences of TM Cys537Stop mutation. The TM domains shown are: D1 = lectin; D2 = EGF-like; D3 = O-glycosylation; D4 = transmembrane; and D5 = cytoplasmic. The Ala473Val mutation in EGF6 was present only in the propositus. The Cys537Stop mutation was present in all 3 family members and resulted in loss of the C-terminal portion of the transmembrane helix and the entire cytoplasmic domain (dotted black line). The consequence of the introduction of a negatively charged C-terminus into the hydrophobic lipid bilayer, together with the loss of stabilizing protein interactions with cytoplasmic domain, resulted in the shedding of TM into the blood plasma.