Fine mapping of low-density lipoprotein receptor gene by genetic linkage on chromosome 19p13.1-p13.3 and study of the founder effect of four French Canadian low-density lipoprotein receptor gene mutations

Familial hypercholesterolemia (FH) is one of the most common autosomal codo minant diseases. FH is caused by mutations in the low-density lipoprotein r eceptor (LDLR) gene and is characterized by raised plasma LDL-cholesterol, tendon xanthomas, and premature coronary heart disease. The frequency of FH among French Canadians in northeastern Quebec is higher than in most other populations, 1:154 vs. 1:500 due to high prevalence of few recurrent mutat ions in the LDLR gene. In the French Canadian population, 11 mutations in t he LDLR gene have been found to occur in geographically diverse areas and a ccount for > 90% of cases. We have first constructed a high-resolution gene tic map to locate several highly polymorphic markers close to LDLR locus, t hus providing the necessary tools to study the origin of the four most comm on mutations which account for approximate to 80% of our FH patients. We ha ve then genotyped five markers (D19S413, D19S865, D19S221, D19S914, D19S586 ) in 102 heterozygotes (38 del > 15kb; 36 W66G; 16 C646Y; 12 E207K), two co mpound heterozygotes (del > 15kb/W66G; del > 15kb/C646Y) and seven homozygo tes (three del > 15 kb; three W66G; one E207K) with FH unrelated to the fir st and second degree. We have found that patients bearing the same LDLR gen e mutation carry a common haplotype at the LDLR locus although there is evi dence for the early occurrence of a recombinational event between the LDLR and the D19S221 locus in the French Canadian patients bearing the W66G muta tion. The fine mapping of LDLR gene close to several highly informative mic rosatellite markers provide fine mapping details of the LDLR region and add itional tools for studies of association between plasma lipoprotein levels and LDLR gene. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.