title: A novel two nucleotide deletion in the apolipoprotein A-I gene, apoA-I Shinbashi, associated with high density lipoprotein deficiency, corneal opacities, planar xanthomas, and premature coronary artery disease.
abstract: Familial HDL deficiency (FHD) is a rare autosomal dominant lipoprotein disorder. We describe a novel genetic variant of the apolipoprotein A-I (apoA-I) gene resulting in FHD. The proband is a 51-year-old woman who was hospitalized due to severe heart failure. Her plasma HDL-cholesterol (C) and apoA-I concentrations were 0.08mmol/l and 1mg/dl, respectively. She exhibited corneal opacities and planar xanthomas on eyelids and elbows. Coronary angiography demonstrated extensive obstructions in two major vessels. Genomic DNA sequencing of the patient's apoA-I gene revealed a homozygosity for a GC deletion between 5 GC repeats in exon 4, creating a frameshift and a stop codon at residue 178. We designated this mutation as apoA-I Shinbashi. The proband's father, son, and daughter were found to be heterozygous for this mutation and their HDL-C and apoA-I levels were about half of normal levels, demonstrating a gene dosage effect. The father underwent coronary bypass surgery at age of 70 years. Lecithin-cholesterol acyltransferase (LCAT) activity was decreased by 63% in the homozygote and 31% in heterozygotes, respectively. This new case of apoA-I deficiency, apoA-I Shinbashi, is the first case involving a single gene defect of the apoA-I gene to develop all the characteristics for apoA-I deficiency, including premature coronary heart disease.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, 105-8461, Tokyo, Japan. kikewaki@jikei.ac.jp
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikewaki
authors.forename: Akira
authors.initials: A
authors.lastname: Matsunaga
authors.forename: Hua
authors.initials: H
authors.lastname: Han
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Akira
authors.initials: A
authors.lastname: Endo
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Tohyama
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kuno
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Mogi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Norio
authors.initials: N
authors.lastname: Tada
authors.forename: Jun
authors.initials: J
authors.lastname: Sasaki
authors.forename: Seibu
authors.initials: S
authors.lastname: Mochizuki
mesh_terms: D000217:Acyltransferases / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood; D003318:Corneal Opacity / Q000235:genetics*; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D006801:Humans; D008075:Lipoproteins, HDL / Q000172:deficiency*; D008875:Middle Aged; D009711:Nucleotides; D014973:Xanthomatosis / Q000235:genetics*
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; D009711:Nucleotides; D000217:Acyltransferases; C056942:lecithin-retinol acyltransferase