MUTATION ANALYSIS REVEALS AN INSERTIONAL HOTSPOT IN EXON-4 OF THE LDLRECEPTOR GENE

Mutation analysis of the low density lipoprotein receptor (LDLR) gene revealed a novel 8-bp duplication after nucleotide 681 in a Costa Rica n patient with familial hypercholesterolaemia. The frameshift caused b y this mutation results in a premature termination codon in the EGF pr ecursor homology domain of the mature LDLR, whereby a truncated protei n of the first 206 residues with an additional 39 abnormal residues wo uld be created, The insertion overlaps with previously described dupli cations of 18 bp and 21 bp, thus revealing an insertional hotspot in e xon 4 of the LDLR gene. We propose that the structural features of thi s region of the LDLR gene contribute significantly to genetic instabil ity and the subsequent DNA duplication via an endogenous sequence-dire cted mechanism of mutagenesis.