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

被引:20
作者
Couture, P
Morissette, J
Gaudet, D
Vohl, MC
Gagné, C
Bergeron, J
Després, JP
Simard, J [1 ]
机构
[1] CHU Laval, Res Ctr, Mol Endocrinol Lab, Quebec City, PQ G1V 4G2, Canada
[2] Univ Laval, Quebec City, PQ G1V 4G2, Canada
[3] CHU Laval, Res Ctr, Lab Hereditary Canc, Quebec City, PQ G1V 4G2, Canada
[4] CHU Laval, Res Ctr, Lipid Res Ctr, Quebec City, PQ G1V 4G2, Canada
[5] Chicoutimi Hosp, Lipid Clin, Chicoutimi, PQ, Canada
基金
英国医学研究理事会;
关键词
genetic linkage mapping; LDLR; familial hypercholesterolemia; French Canadians;
D O I
10.1016/S0021-9150(98)00267-6
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Familial hypercholesterolemia (FH) is one of the most common autosomal codominant diseases. FH is caused by mutations in the low-density lipoprotein receptor (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 mutations in the LDLR gene. In the French Canadian population, 11 mutations in the LDLR gene have been found to occur in geographically diverse areas and account for > 90% of cases. We have first constructed a high-resolution genetic map to locate several highly polymorphic markers close to LDLR locus, thus providing the necessary tools to study the origin of the four most common mutations which account for approximate to 80% of our FH patients. We have then genotyped five markers (D19S413, D19S865, D19S221, D19S914, D19S586) in 102 heterozygotes (38 del > 15kb; 36 W66G; 16 C646Y; 12 E207K), two compound heterozygotes (del > 15kb/W66G; del > 15kb/C646Y) and seven homozygotes (three del > 15 kb; three W66G; one E207K) with FH unrelated to the first and second degree. We have found that patients bearing the same LDLR gene mutation carry a common haplotype at the LDLR locus although there is evidence for the early occurrence of a recombinational event between the LDLR and the D19S221 locus in the French Canadian patients bearing the W66G mutation. The fine mapping of LDLR gene close to several highly informative microsatellite markers provide fine mapping details of the LDLR region and additional tools for studies of association between plasma lipoprotein levels and LDLR gene. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.
引用
收藏
页码:145 / 151
页数:7
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