Functional Characterization and Classification of Frequent Low-Density Lipoprotein Receptor Variants

Hum Mutat. 2015 Jan;36(1):129-41. doi: 10.1002/humu.22721. Epub 2014 Nov 27.


Familial hypercholesterolemia (FH) is an autosomal-dominant disorder mostly caused by mutations in the low-density lipoprotein receptor (LDLR) gene leading to increased risk for premature cardiovascular diseases. According to functional studies, LDLR mutations may be classified into five classes. The main objective of this study was to characterize seven LDLR variants previously detected in FH patients. Analysis by flow cytometry and confocal microscopy of LDLR activity demonstrate that all the studied variants are pathogenic. Among the mutations located in β-propeller, p.Trp577Gly and p.Ile624del were classified as class 2, whereas p.Arg416Trp and p.Thr454Asn as class 5. p.Phe800Glyfs*129 (located in the cytoplasmic domain), p.Cys155Tyr (located in the binding domain), and p.Asn825Lys (inside FxNPxY motif) were classified as class 2, 3, and 4, respectively. The results also show that LDLR activity of these class 4 and 5 variants is not completely abolished, showing a milder phenotype. We have also determined that statin response is more efficient lowering total cholesterol in heterozygous patients carrying p.Ile624del (class 2) compared with p.Arg416Trp and p.Thr454Asn (class 5) variants. In conclusion, these findings emphasize the importance of characterizing LDLR pathogenic variants to provide an indisputable FH diagnosis and to gain insight into the statin response depending on the LDLR class mutation.

Keywords: LDRL; familial hypercholesterolemia; mutation class defect; mutations; statins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • CHO Cells
  • Cricetulus
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Hyperlipoproteinemia Type II / drug therapy*
  • Hyperlipoproteinemia Type II / genetics*
  • Hypolipidemic Agents / therapeutic use*
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Protein Structure, Tertiary
  • Receptors, LDL / chemistry*
  • Receptors, LDL / genetics*
  • Receptors, LDL / metabolism


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypolipidemic Agents
  • LDLR protein, human
  • Receptors, LDL