A novel deletion/inversion mutation in the low-density lipoprotein receptor gene as a cause of heterozygous familial hypercholesterolemia.

A combined deletion/inversion rearrangement of the LDL receptor gene was discovered in a Finnish patient with heterozygous familial hypercholesterolemia (FH). Sequence analysis of the mutated allele revealed an insertion of 4 nucleotides in exon 11, caused by a combined deletion and insertion event replacing a 13-bp segment of the normal exon 11 sequence of the LDL receptor gene by a 17-bp stretch of new sequence at the deletion breakpoint. The inserted sequence was identical to the normal exon 9 sequence of the LDL receptor gene from nt1225 to nt1241 inserted in an inverted orientation. This defect causes a translational frameshift after amino acid 525 (glycine) and leads to a premature termination codon at amino acid position 538. Analysis of reverse transcriptase-PCR products from total RNA extracted from cultured fibroblasts revealed only transcripts encoded by the normal allele. This finding was consistent with the reduced functional activity of the LDL receptor found in the fibroblasts of the patient to levels less than 50% of those in normal cells. In conclusion, we have identified a complex and hitherto unreported type of rearrangement of the human LDL receptor gene. The precise mechanism of this mutation (designated as FH-Jalasjärvi) remains obscure, although it may involve complex loop formation by interaction of complementary sequences present in the mutation breakpoints and their immediate flanking regions.