2 NOVEL FRAMESHIFT MUTATIONS IN THE LOW-DENSITY-LIPOPROTEIN RECEPTOR GENE GENERATED BY ENDOGENOUS SEQUENCE-DIRECTED MECHANISMS

DNA samples from 60 unrelated Belgian hypercholesterolemic patients we re subjected to heteroduplex analysis of exon 4 of the low density lip oprotein receptor (LDLR) gene. Aberrant mobility bands were detected i n 2 patients and the underlying mutations were characterized by DNA se quence analysis. Both mutations, a 19-bp insertion at codon 141 and a 23-bp deletion at codon 168, produce premature stop codons in the high ly conserved ligand binding domain of the mature LDLR. Sequence data i ndicated that mispairing between short direct repeats during DNA repli cation is the most probable mechanism by which these mutations could h ave arisen. Our observations are consistent with an endogenous sequenc e-directed mechanism of mutagenesis.