No genetic linkage or molecular evidence for involvement of the PCSK9, ARH or CYP7A1 genes in the Familial Hypercholesterolemia phenotype in a sample of Danish families without pathogenic mutations in the LDL receptor and apoB genes

Atherosclerosis. 2004 Dec;177(2):415-22. doi: 10.1016/j.atherosclerosis.2004.07.028.


A locus on chromosome 1p34.1-p32 has been linked to autosomal dominant Familial Hypercholesterolemia (FH) and is termed the third FH locus. We tested whether this third FH locus is linked to the FH phenotype in 20 Danish families, with 158 members, without pathogenic mutations in the genes, encoding the low-density lipoprotein (LDL) receptor or apolipoprotein B (apoB). We could exclude the third FH locus as a cause of FH by genetic linkage analysis in the families taken together. Since haplotype analysis of each family nevertheless suggested that the FH phenotype co-segregated in a manner consistent with linkage to the third FH locus in three small pedigrees, we performed sequencing analysis without being able to demonstrate mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, the main candidate gene in the third FH locus. By the same combination of genetic linkage and molecular analysis we could also exclude mutations in the gene for the LDL receptor adaptor protein and in the gene for cholesterol-7-alpha-hydroxylase as causes of FH in our sample. Although not indicating linkage to any known loci, our data still indicate that another dominant gene may be involved in causing a FH phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adult
  • Aged
  • Apolipoproteins B / genetics*
  • Cholesterol 7-alpha-Hydroxylase / genetics*
  • Female
  • Genetic Linkage*
  • Humans
  • Hyperlipoproteinemia Type II / genetics*
  • Male
  • Middle Aged
  • Mutation*
  • Phenotype
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Receptors, LDL / genetics*
  • Serine Endopeptidases / genetics*


  • Adaptor Proteins, Signal Transducing
  • Apolipoproteins B
  • LDLRAP1 protein, human
  • Receptors, LDL
  • Cholesterol 7-alpha-Hydroxylase
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases