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

• Published in: Atherosclerosis 2004, Vol.172 (1), p.39-45
• Main Authors: Ikewaki, Katsunori, Matsunaga, Akira, Han, Hua, Watanabe, Hisayuki, Endo, Akira, Tohyama, Jun-ichiro, Kuno, Mamoru, Mogi, Jun-ichi, Sugimoto, Ken-ichi, Tada, Norio, Sasaki, Jun, Mochizuki, Seibu
• Format: Article
• Language: English
• Subjects: Acyltransferases - metabolism; apoA-I; Apolipoprotein A-I - blood; Apolipoprotein A-I - genetics; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cholesterol, HDL - blood; Corneal opacities; Corneal Opacity - genetics; Coronary Angiography; Coronary artery disease; Coronary Artery Disease - genetics; Female; Gene Deletion; Gene Dosage; HDL deficiency; Humans; Lipoproteins, HDL - deficiency; Medical sciences; Middle Aged; Nucleotides; Xanthomas; Xanthomatosis - genetics
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2003.09.024

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 0.08 mmol/l and 1 mg/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.