Apolipoprotein A-I Q[-2]X causing isolated apolipoprotein A-I deficiency in a family with analphalipoproteinemia.

Abstract

We report a Canadian kindred with a novel mutation in the apolipoprotein (apo) A-I gene causing analphalipoproteinemia. The 34-yr-old proband, product of a consanguineous marriage, had bilateral retinopathy, bilateral cataracts, spinocerebellar ataxia, and tendon xanthomata. High density lipoprotein cholesterol (HDL-C) was < 0.1 mM and apoA-I was undetectable. Genomic DNA sequencing of the proband's apoA-I gene identified a nonsense mutation at codon [-2], which we designate as Q[-2]X. This mutation causes a loss of endonuclease digestion sites for both BbvI and Fnu4HI. Genotyping identified four additional homozygotes, four heterozygotes, and two unaffected subjects among the first-degree relatives. Q[-2]X homozygosity causes a selective failure to produce any portion of mature apoA-I, resulting in very low plasma level of HDL. Heterozygosity results in approximately half-normal apoA-I and HDL. Gradient gel electrophoresis and differential electroimmunodiffusion assay revealed that the HDL particles of the homozygotes had peak Stokes diameter of 7.9 nm and contained apoA-II without apoA-I (Lp-AII). Heterozygotes had an additional fraction of HDL3-like particles. Two of the proband's affected sisters had documented premature coronary heart disease. This kindred, the third reported apoA-I gene mutation causing isolated complete apoA-I deficiency, appears to be at significantly increased risk for atherosclerosis.

• Authors: D S Ng, L A Leiter, C Vezina, P W Connelly, R A Hegele
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 93 Issue 1 Pg. 223-9 (Jan 1994) ISSN: 0021-9738 [Print] United States
• PMID: 8282791 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein A-I
• Apolipoproteins
• Cholesterol, HDL
• Cholesterol, LDL
• Cholesterol, VLDL
• Codon
• DNA Primers
• Lipoproteins, HDL
• Triglycerides
• DNA
• Cholesterol

Topics

• Adolescent
• Adult
• Amino Acid Sequence
• Apolipoprotein A-I (deficiency, genetics)
• Apolipoproteins (analysis, metabolism)
• Base Sequence
• Cholesterol (blood)
• Cholesterol, HDL (blood)
• Cholesterol, LDL (blood)
• Cholesterol, VLDL (blood)
• Cloning, Molecular
• Codon (genetics)
• Consanguinity
• DNA (analysis)
• DNA Primers
• Exons
• Female
• Humans
• Lipoproteins, HDL (deficiency)
• Male
• Molecular Sequence Data
• Pedigree
• Point Mutation
• Polymerase Chain Reaction
• Triglycerides (blood)