title: A combined LDL receptor/LDL receptor adaptor protein 1 mutation as the cause for severe familial hypercholesterolemia.
abstract: Familial hypercholesterolemia (FH) results from impaired catabolism of plasma low density lipoproteins (LDL), thus leading to high cholesterol, atherosclerosis, and a high risk of premature myocardial infarction. FH is commonly caused by defects of the LDL receptor or its main ligand apoB, together mediating cellular uptake and clearance of plasma LDL. In some cases FH is inherited by mutations in the genes of PCSK9 and LDLRAP1 (ARH) in a dominant or recessive trait. The encoded proteins are required for LDL receptor stability and internalization within the LDLR pathway. To detect the underlying genetic defect in a family of Turkish descent showing unregular inheritance of severe FH, we screened the four candidate genes by denaturing gradient gel electrophoresis (DGGE) mutation analysis. We identified different combinatory mixtures of LDLR- and LDLRAP1-gene defects as the cause for severe familial hypercholesterolemia in this family. We also show for the first time that a heterozygous LDLR mutation combined with a homozygous LDLRAP1 mutation produces a more severe hypercholesterolemia phenotype in the same family than a homozygous LDLR mutation alone.
authors.affiliation: Department of Internal Medicine, Cardiology, Philipps University, D-35033 Marburg, Germany. soufi@staff.uni-marburg.de
authors.forename: Muhidien
authors.initials: M
authors.lastname: Soufi
authors.forename: Stephan
authors.initials: S
authors.lastname: Rust
authors.forename: Michael
authors.initials: M
authors.lastname: Walter
authors.forename: Juergen R
authors.initials: JR
authors.lastname: Schaefer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000595:Amino Acid Sequence; D002675:Child, Preschool; D005260:Female; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011973:Receptors, LDL / Q000235:genetics*; D014421:Turkey
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C573412:LDLR protein, human; C469745:LDLRAP1 protein, human; D011973:Receptors, LDL