INDEPENDENT MUTATIONS AT CODON-3500 OF THE APOLIPOPROTEIN-B GENE ARE ASSOCIATED WITH HYPERLIPIDEMIA

The apoB arginine-to-glutamine change at codon 3500 has become establi shed as a cause of failure of binding of the LDL particle to its recep tor and the consequent hypercholesterolemia of familial defective apoB 100. A search for further similar mutations was undertaken by systema tic screening of a candidate region of the apoB gene from individuals with hypercholesterolemia. Polymerase chain reaction and denaturing gr adient gel electrophoresis were used. We describe two families in whic h a different mutation in the codon 3500 causes an arginine-to-tryptop han substitution. Most adults in these families who have this mutation have hypercholesterolemia. LDL derived from all who have inherited th e mutation is dysfunctional in that it allows only poor growth of an L DL cholesterol- dependent cell line. We conclude that this arginine 35 00 is essential to the function of apoB and that its loss and replacem ent by glutamine or tryptophan is responsible for the hypercholesterol emia of familial defective apoB 100.