A combined LDL receptor/LDL receptor adaptor protein 1 mutation as the cause for severe familial hypercholesterolemia

• Published in: Gene 2013-05, Vol.521 (1), p.200-203
• Main Authors: Soufi, Muhidien, Rust, Stephan, Walter, Michael, Schaefer, Juergen R.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Amino Acid Sequence; ARH deficiency; atherosclerosis; Autosomal recessive hypercholesterolemia; Child, Preschool; cholesterol; denaturing gradient gel electrophoresis; Female; genes; genetic disorders; heterozygosity; homozygosity; Homozygote; Humans; hypercholesterolemia; Hyperlipoproteinemia Type II - drug therapy; Hyperlipoproteinemia Type II - etiology; Hyperlipoproteinemia Type II - genetics; LDLR defect; LDLRAP1; low density lipoprotein; Male; metabolism; Molecular Sequence Data; Mutation; myocardial infarction; Pedigree; phenotype; Receptors, LDL - genetics; risk; Turkey
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2013.03.034

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. •We identified a combined LDLR/LDLRAP1 mutation in a Turkish FH-family.•The combined LDLR p.Q233P and LDLRAP1 p.G136X mutation leads to early onset CHD.•Unique genetic combinations correlate with the severity of FH in the family.•Homozygosity for LDLR p.G136X is less severe than for LDLRAP1 p.Q233P.•Aggressive lipid lowering therapy is not sufficient in LDLRAP1 deficiency.