title: A double mutant [N543H+2393del9] allele in the LDL receptor gene in familial hypercholesterolemia: effect on plasma cholesterol levels and cardiovascular disease.
abstract: Familial hypercholesterolemia is a genetic disorder caused by mutations in the LDL receptor gene. During a survey of mutations of LDL receptor gene in Spanish FH patients we found two mutations in the same allele: a missense N543H mutation in exon 11 and a 9bp inframe deletion (2393del9) located in exon 17. This double mutant allele was founded in 10 out of 458 unrelated patients: one homozygous FH [N543H+2393del9] + [N543H+2393del9], one compound heterozygote [N543H+2393del9] + [W-18X+E256K] and 8 heterozygotes. Flow cytometric analysis showed a defective LDL binding (20% of normal value) and internalization (23%) in lymphocytes from the homozygous patient; furthermore, studies of mitogen-stimulated lymphocytes demonstrated that the ability of LDL to support cell proliferation was impaired. Unexpectedly, not all carriers of the double mutant allele develop hypercholesterolemia and, furthermore, cholesterol-lowering treatment of the homozygous patient resulted in a 58% LDL cholesterol reduction. In conclusion, the phenotypic expression in the homozygous and heterozygous patients presented here, as well as the LDL-receptor residual activity, allowed the classification of this mutation as mild extending the group of mild mutations found at homozygosity.
authors.affiliation: Departamento de Bioquimica y Biologia Molecular y Celular, Universidad de Zaragoza, Zaragoza.
authors.forename: S
authors.initials: S
authors.lastname: Castillo
authors.forename: G
authors.initials: G
authors.lastname: Reyes
authors.forename: D
authors.initials: D
authors.lastname: Tejedor
authors.forename: P
authors.initials: P
authors.lastname: Mozas
authors.forename: Y
authors.initials: Y
authors.lastname: Suarez
authors.forename: M A
authors.initials: MA
authors.lastname: Lasuncion
authors.forename: A
authors.initials: A
authors.lastname: Cenarro
authors.forename: F
authors.initials: F
authors.lastname: Civeira
authors.forename: R
authors.initials: R
authors.lastname: Alonso
authors.forename: P
authors.initials: P
authors.lastname: Mata
authors.forename: M
authors.initials: M
authors.lastname: Pocovi
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D002318:Cardiovascular Diseases / Q000097:blood; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics*; D017384:Sequence Deletion; D014280:Triglycerides / Q000097:blood
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D011973:Receptors, LDL; D014280:Triglycerides; D004247:DNA; D002784:Cholesterol