LDLR – Familial Hypercholesterolemia Type 1

LDLR (low-density lipoprotein receptor) plays a central role in hepatic clearance of LDL-cholesterol, and its haploinsufficiency causes Autosomal Dominant Hypercholesterolemia (Familial Hypercholesterolemia Type 1) (MONDO:0007750). Pathogenic variants reduce receptor levels at the hepatocyte surface, leading to lifelong elevations in LDL-cholesterol and early-onset cardiovascular disease. The condition is inherited in an autosomal dominant pattern with high penetrance.

Extensive genetic screening has cataloged 683 distinct LDLR alleles worldwide, comprising missense, nonsense, splice-site, frameshift, and major rearrangement variants (PMID:11137106). In a French ADH cohort of 1358 probands, LDLR mutations were identified in 1003 subjects, representing 391 unique events: missense (46.0%), frameshift (14.6%), splice-site (13.6%), nonsense (11.3%), and large rearrangements (9.7%) (PMID:20809525). This allelic heterogeneity underscores the strong genetic contribution of LDLR to familial hypercholesterolemia.

Key variant classes include intronic splice disruptions (e.g., c.1358+1G>A) and exonic substitutions affecting ligand binding (e.g., c.418G>A (p.Glu140Lys)). Founder and recurrent alleles have been reported across diverse populations, reflecting both private mutations and population-specific enrichment.

Segregation analysis in an eight-generation Utah kindred demonstrated co-segregation of the IVS14+1G>A splice-site mutation with elevated LDL-cholesterol in 73 affected relatives, while non-carriers maintained normal lipid profiles (PMID:12740481). This large-scale familial evidence confirms causality.

Functional assays corroborate loss-of-function as the primary mechanism. The Glu119Lys variant impairs receptor processing and abolishes LDL uptake in COS-7 cells (PMID:7981713), whereas W23X and W66G mutations produce receptor-negative (class I) and recycling-defective (class V) phenotypes in lymphocyte assays (PMID:10735631). These studies validate the predicted impact of LDLR variants on cholesterol metabolism.

Given the breadth of genetic and experimental concordance, LDLR is classified as having a Definitive association with Familial Hypercholesterolemia Type 1. LDLR variant testing is essential for accurate diagnosis, cascade family screening, risk stratification, and guiding lipid-lowering therapy.

References

• Journal of atherosclerosis and thrombosis • 2003 • Apolipoprotein H variant modifies plasma triglyceride phenotype in familial hypercholesterolemia: a molecular study in an eight-generation hyperlipidemic family PMID:12740481
• Human Mutation • 2010 • Molecular spectrum of autosomal dominant hypercholesterolemia in France PMID:20809525
• Atherosclerosis • 2001 • Low-density lipoprotein receptor gene (LDLR) world-wide website in familial hypercholesterolaemia: update, new features and mutation analysis PMID:11137106
• Human Mutation • 1994 • Characterization of a disease-causing Glu119-Lys mutation in the low-density lipoprotein receptor gene in two Danish families with heterozygous familial hypercholesterolemia PMID:7981713
• Clinical Genetics • 2000 • Functional characterization of two low density lipoprotein receptor gene mutations by fluorescence flow cytometric assessment of receptor activity in stimulated human T-lymphocytes PMID:10735631

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