3-DIMENSIONAL STRUCTURE OF THE LDL RECEPTOR-BINDING DOMAIN OF THE HUMAN APOLIPOPROTEIN E2 (ARG(136)-]CYS) VARIANT

The familial lipoprotein disorder type III hyperlipoproteinemia (HLP) is usually inherited as a recessive trait. Indeed, more than 90% of af fected individuals are homozygous for a receptor binding-defective iso form of apolipoprotein (ape) E, apo E2. However, some rare apo E varia nts have been described that dominantly (thus in a single dose) predis pose to the disease. Amino acid substitutions, which are accompanied w ith the loss of positive charges within the proposed apo E binding-reg ion to lipoprotein receptors, seem to be responsible in most of these cases for the dominance with respect to the expression of type III HLP . So far available data in the literature on the naturally occurring h uman apo E2 (Arg(136) --> Cys) variant are not conclusive about its re cessive or dominant character. We recently identified a subject hetero zygous for this mutation, presenting the typical clinical and biochemi cal characteristics of type III HLP. In the present study we performed further analysis of the mutation on apo E structure and function base d on computer modeling. Our combined data point to a dominant influenc e of the apo E2 (Arg(136) --> Cys) variant with respect to the transmi ssion of the disease.