IDENTIFICATION OF 2 NOVEL LDL RECEPTOR GENE DEFECTS IN FRENCH-CANADIAN PEDIATRIC POPULATION - MUTATIONAL ANALYSIS AND BIOCHEMICAL-STUDIES

Familial hypercholesterolemia (FH) is at least twofold more prevalent in French Canadians from Quebec than in most Western populations. Alth ough our recent data confirmed this high frequency of heterozygous FH in our pediatric population with hypercholesterolemia, none of the fiv e established molecular defects for the French Canadian population was detected in 29% of the unrelated French-Canadian children characteriz ed by a persistent increase in LDL (low density lipoprotein receptor) cholesterol and a positive parental history of hyperlipidemia (Assouli ne et al., 1995). To probe for new mutations, six of these molecularly undiagnosed children were investigated as index patients. By using si ngle-strand conformation polymorphism analysis and DNA sequencing, two never mutations were identified in two of these subjects: (1) 7-base pair (bp) duplication following nucleotide 681 (according to the cDNA sequence) in exon 4 (681ins7), which causes a frameshift, the introduc tion of a stop at codon 208, and premature chain termination, and (2) A to G change in exon 8 substituting a tyrosine for a cysteine at amin o acid 354 (Y354C). A third subject carried the recently reported exon 10 mutation (Y468X), whereas the remaining three patients demonstrate d various known polymorphisms with no effect on gene product Rapid mol ecular assays were developed to detect the two new mutations as well a s the Y468X mutation. Screening of our cohort showed heterozygosity in 1/88, in 2/88, and in 2/88 of patients for the 681ins7, the Y354C, an d the Y468X mutations, respectively. (C) 1997 Wiley-Liss, Inc.