LDLreceptormutationen

LDL receptor mutations, often described as LDLR mutations, are genetic alterations in the LDLR gene that disrupt the function of the hepatic LDL receptor and cause familial hypercholesterolemia (FH). Inheritance is typically autosomal dominant; heterozygous FH is relatively common in many populations (roughly 1 in 200–500), while homozygous FH is rare and associated with markedly elevated LDL cholesterol from birth.

The LDLR gene encodes the LDL receptor, which binds apolipoprotein B-100 on LDL particles and mediates receptor-mediated endocytosis in the liver. Most pathogenic variants are loss-of-function: missense, nonsense, frameshift, splice-site changes, or deletions that impair synthesis, trafficking to the cell surface, ligand binding, or recycling of the receptor. The result is reduced hepatic uptake of LDL and elevated plasma LDL cholesterol, which increases the risk of atherosclerotic cardiovascular disease from an early age.

Clinical features vary by genotype. Heterozygous FH typically presents with elevated LDL-C and may show tendon xanthomas or corneal arcus in adults, with an increased risk of premature cardiovascular disease. Homozygous FH presents with very high LDL-C levels in childhood and early, often severe, cardiovascular events. Diagnosis integrates lipid levels, family history, and clinical signs using criteria such as the Simon Broome or Dutch Lipid Clinic Network criteria; genetic testing confirming an LDLR pathogenic variant supports the diagnosis.

Management focuses on lowering LDL-C to target levels and reducing cardiovascular risk. Treatments include high-intensity statins plus ezetimibe, with PCSK9 inhibitors, bempedoic acid, or other agents as needed. In severe or homozygous cases, lomitapide or mipomersen and LDL apheresis may be employed. Cascade screening of relatives is recommended to identify affected individuals. Ongoing research explores gene therapy and LDLR-targeted therapies to improve outcomes.