Functional characterization of mutant genes associated with autosomal dominant familial hypercholesterolemia: integration and evolution of genetic diagnosis

Nutr Metab Cardiovasc Dis. 2015 Nov;25(11):979-87. doi: 10.1016/j.numecd.2015.06.007. Epub 2015 Jun 23.


Aims: Familial Hypercholesterolemia (FH) is one of the most frequent dyslipidemias, the autosomal dominant form of which is primarily caused by mutations in the LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes, although in around 20% of patients the genetic cause remains unidentified. Genetic testing has notably improved the identification of patients suffering from FH, the most frequent cause of which is the presence of mutations in the LDLR gene. Although more than 1200 different mutations have been identified in this gene, about 80% are recognized to be pathogenic. We aim to overview the current methods used to perform the functional characterization of mutations causing FH and to highlight the conditions requiring a functional characterization of the variant in order to obtain a diagnostic report.

Data synthesis: In the current review, we summarize the different types of functional assays - including their advantages and disadvantages - performed to characterize mutations in the LDLR, APOB and PCSK9 genes helping to better define their pathogenic role. We describe the evaluation of splicing alterations and two major procedures for functional characterization: 1. ex vivo methods, using cells from FH patients; 2. in vitro methods using cell lines.

Conclusions: Functional characterization of the LDLR, APOB and PCSK9 mutant genes associated with FH can be considered a necessary integration of its genetic diagnosis.

Keywords: APOB; Diagnostic tools; Familial hypercholesterolemia; Functional assay; LDLR; Mutation pathogenicity; PCSK9.

Publication types

  • Review

MeSH terms

  • Apolipoprotein B-100 / genetics
  • DNA Mutational Analysis / methods
  • Genetic Testing / methods*
  • Humans
  • Hyperlipoproteinemia Type II / diagnosis*
  • Hyperlipoproteinemia Type II / genetics*
  • Mutation
  • Proprotein Convertase 9
  • Proprotein Convertases / genetics
  • Receptors, LDL / genetics
  • Serine Endopeptidases / genetics


  • APOB protein, human
  • Apolipoprotein B-100
  • Receptors, LDL
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases