A SINGLE-POINT MUTATION IN THE SPLICE DONOR SITE OF THE LOW-DENSITY-LIPOPROTEIN-RECEPTOR GENE PRODUCES INTRON READ-THROUGH, EXON-SKIPPED AND CRYPTIC-SITE-UTILIZED TRANSCRIPTS

Familial hypercholesterolemia is a genetic disorder caused by mutation s of the low-density-lipoprotein (LDL) receptor gene. We characterized the structures of LDL receptor mRNA transcripts in the fibroblasts of a homozygous patient carrying a single base substitution (T-->C) at t he 5' splice donor site of intron 12 of the LDL receptor gene. We iden tified three aberrant transcripts as a consequence of intron-12 read-t hrough, exon-12 skipping and utilization of a cryptic splice donor sit e. Only a point mutation at the 5' splice donor site caused the produc tion of three alternatively spliced products. None of these transcript s produced a functional LDL receptor protein in this patient.