MOLECULAR CHARACTERIZATION OF MINOR GENE REARRANGEMENTS IN FINNISH PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA - IDENTIFICATION OF 2 COMMON MISSENSE MUTATIONS (GLY823-]ASP AND LEU380-]HIS) AND 8 RARE MUTATIONS OF THE LDL RECEPTOR GENE

Two deletions of the low-density lipoprotein (LDL) receptor gene were previously shown to account for about two thirds of all mutations caus ing familial hypercholesterolemia (FH) in Finland. We screened the DNA samples from a cohort representing the remaining 30% of Finnish heter ozygous FH patients by amplifying all the 18 exons of the receptor gen e by PCR and searching for DNA variations with the SSCP technique. Ten novel mutations were identified, comprising two nonsense and seven mi ssense mutations as well as one frameshift mutation caused by a 13-bp deletion. A single nucleotide change, substituting adenine for guanidi ne at position 2533 and resulting in an amino acid change of glycine t o aspartic acid at codon 823, was found in DNA samples from 14 unrelat ed FH probands. This mutation (FH-Turku) affects the sequence encoding the putative basolateral sorting signal of the LDL receptor protein; however, the exact functional consequences of this mutation are yet to be examined. The PH-Turku gene and another point mutation (Leu380-->H is or FH-Pori) together account for similar to 8% of the FH-causing ge nes in Finland and are particularly common among FH patients from the southwestern part of the country (combined, 30%). Primer-introduced re striction analysis was applied for convenient assay of the FH-Turku an d FH-Pori point mutations. In conclusion, this paper demonstrates the unique genetic background of FH in Finland and describes a commonly oc curring FH gene with a missense mutation closest to the C terminus thu s far reported.