Deletion in the gene for the low-density-lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia.

We found a large deletion (more than 10 kilobases) in the gene for the low-density-lipoprotein receptor in 63 percent of French Canadians with heterozygous familial hypercholesterolemia. The deletion also occurred in homozygous form in four of seven French Canadian homozygotes. The deletion removes the promoter and first exon of the gene, and it abolishes the production of messenger RNA for the low-density-lipoprotein receptor. The high frequency of this mutation is presumably related to a founder effect among the 8000 ancestors of present-day French Canadians, who have had relatively little cross-breeding with groups of other national origins. This deletion has not been observed in any other ethnic group. It can be detected by analysis of genomic DNA from blood leukocytes, thus allowing direct diagnosis of familial hypercholesterolemia in a majority of affected French Canadians.

[1]  D. Russell,et al.  Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia , 1987, Cell.

[2]  D. Russell,et al.  The Lebanese allele at the low density lipoprotein receptor locus. Nonsense mutation produces truncated receptor that is retained in endoplasmic reticulum. , 1987, The Journal of biological chemistry.

[3]  S. Antonarakis,et al.  Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots , 1986, Nature.

[4]  H. Hobbs,et al.  Deletion of exon encoding cysteine-rich repeat of low density lipoprotein receptor alters its binding specificity in a subject with familial hypercholesterolemia. , 1986, The Journal of biological chemistry.

[5]  T. Südhof,et al.  The LDL receptor in familial hypercholesterolemia: use of human mutations to dissect a membrane protein. , 1986, Cold Spring Harbor symposia on quantitative biology.

[6]  R. Gregg,et al.  The association of LDL receptor activity, LDL cholesterol level, and clinical course in homozygous familial hypercholesterolemia. , 1985, Metabolism: clinical and experimental.

[7]  E. Chen,et al.  Detection and sequence of mutations in the factor VIII gene of haemophiliacs          , 1985, Nature.

[8]  C. Caskey,et al.  HPRT: gene structure, expression, and mutation. , 1985, Annual review of genetics.

[9]  D. Russell,et al.  Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. , 1985, Annual review of cell biology.

[10]  G. Church,et al.  Genomic sequencing. , 1993, Methods in molecular biology.

[11]  G. Steiner,et al.  Familial hypercholesterolemia: report of coronary death at age 3 in a homozygous child and prenatal diagnosis in a heterozygous sibling. , 1982, The Journal of pediatrics.

[12]  K. Paigen,et al.  A simple, rapid, and sensitive DNA assay procedure. , 1980, Analytical biochemistry.

[13]  R. Lees,et al.  Homozygous Familial Hypercholesterolemia , 1975 .

[14]  A. Khachadurian,et al.  Experiences with the homozygous cases of familial hypercholesterolemia. A report of 52 patients. , 1973, Nutrition and metabolism.