title: 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.affiliation: Department of Medicine, St. Michael's Hospital, University of Toronto, Ontario, Canada.
authors.forename: D S
authors.initials: DS
authors.lastname: Ng
authors.forename: L A
authors.initials: LA
authors.lastname: Leiter
authors.forename: C
authors.initials: C
authors.lastname: Vezina
authors.forename: P W
authors.initials: PW
authors.lastname: Connelly
authors.forename: R A
authors.initials: RA
authors.lastname: Hegele
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D016632:Apolipoprotein A-I / Q000172:deficiency* / Q000235:genetics*; D001053:Apolipoproteins / Q000032:analysis / Q000378:metabolism*; D001483:Base Sequence; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D003001:Cloning, Molecular; D003062:Codon / Q000235:genetics; D003241:Consanguinity; D004247:DNA / Q000032:analysis; D017931:DNA Primers; D005091:Exons; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000172:deficiency*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood
chemical_list: D016632:Apolipoprotein A-I; D001053:Apolipoproteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D003062:Codon; D017931:DNA Primers; D008075:Lipoproteins, HDL; D014280:Triglycerides; D004247:DNA; D002784:Cholesterol