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Published on: September 15, 2018
A combined LDL receptor/LDL receptor adaptor protein 1 mutation as the cause for severe familial hypercholesterolemia
Muhidien Soufi1, Stephan Rust, Michael Walter
1Department of Internal Medicine, Cardiology, Philipps University, D-35033 Marburg, Germany. soufi@staff.uni-marburg.de
Insights
Familial hypercholesterolemia (FH) is caused by genetic defects. This study found combined LDLR and LDLRAP1 gene mutations cause severe FH, with compound heterozygosity leading to a worse phenotype.
Area of Science:
- Genetics
- Biochemistry
- Cardiovascular Medicine
Background:
- Familial hypercholesterolemia (FH) involves impaired low-density lipoprotein (LDL) catabolism, leading to high cholesterol, atherosclerosis, and premature heart attacks.
- Genetic defects in the LDL receptor (LDLR) or its ligand apoB are common causes of FH.
- Mutations in PCSK9 and LDLRAP1 (ARH) genes, affecting LDL receptor stability and internalization, can also cause FH.
Observation:
- A Turkish family with unusual severe FH inheritance patterns was investigated.
- Genetic screening of four candidate genes was performed using denaturing gradient gel electrophoresis (DGGE).
- The study identified combined defects in LDLR and LDLRAP1 genes as the cause of severe FH in this family.
Findings:
- Different combinations of LDLR and LDLRAP1 gene defects were identified as the cause of severe FH.
- A heterozygous LDLR mutation combined with a homozygous LDLRAP1 mutation resulted in a more severe hypercholesterolemia phenotype than a homozygous LDLR mutation alone.
- This is the first study to demonstrate this compound genetic effect on FH severity.
Implications:
- Understanding combined genetic defects in FH can improve diagnosis and risk assessment.
- Identifying specific gene mutations allows for tailored treatment strategies.
- This research highlights the complex genetic underpinnings of severe 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.
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