A novel mutation of the apolipoprotein A-I gene in a family with familial combined hyperlipidemia

Atherosclerosis. 2008 May;198(1):145-51. doi: 10.1016/j.atherosclerosis.2007.09.017. Epub 2007 Oct 24.


We report a large family in which four members showed a plasma lipid profile consistent with the clinical diagnosis of familial combined hyperlipidemia (FCHL). One of these patients was found to have markedly reduced HDL cholesterol (HDL-C) (0.72 mmol/l) and Apo A-I (72 mg/dl) levels, a condition suggestive of the presence of a mutation in one of the HDL-related genes. The analysis of APOA1 gene revealed that this patient was heterozygous for a cytosine insertion in exon 3 (c.49-50 ins C), resulting in a frame-shift and premature stop codon at position 26 of pro-Apo A-I (Q17PFsX10). This novel mutation, which prevents the synthesis of Apo A-I, was also found in four family members, including three siblings and the daughter of the proband. Carriers of Apo A-I mutation had significantly lower HDL-C and Apo A-I than non-carriers family members (0.77+/-0.15 mmol/l vs. 1.15+/-0.20 mmol/l, P<0.005; 71.4+/-9.1mg/dl vs. 134.0+/-14.7 mg/dl, P<0.005, respectively). Two of the APOA1 mutation carriers, who were also heavy smokers, had fibrous plaques in the carotid arteries causing mild stenosis (20%). The intimal-media thickness in the two other adult carriers was within the normal range. The other non-carriers family members with FCHL had either overt vascular disease or carotid atherosclerosis at ultrasound examination. This observation suggests that the low HDL-C/low Apo A-I phenotype may result from a genetic defect directly affecting HDL metabolism, even in the context of a dyslipidemia which, like FCHL, is associated with low plasma HDL-C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Apolipoprotein A-I / genetics*
  • Apolipoproteins B / genetics
  • Carotid Artery Diseases / diagnostic imaging
  • Carotid Artery Diseases / genetics
  • Carotid Artery Diseases / pathology
  • Cholesterol, HDL / blood
  • Cholesterol, HDL / deficiency
  • Codon, Nonsense
  • Esterification
  • Family Health
  • Female
  • Frameshift Mutation*
  • Humans
  • Hyperlipidemia, Familial Combined / genetics*
  • Lipids / blood
  • Male
  • Middle Aged
  • Pedigree
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Receptors, LDL / genetics
  • Serine Endopeptidases / genetics
  • Smoking
  • Ultrasonography


  • Apolipoprotein A-I
  • Apolipoproteins B
  • Cholesterol, HDL
  • Codon, Nonsense
  • Lipids
  • Receptors, LDL
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases