A Novel Homozygous Missense Mutation in the Apo A-I Gene With Apo A-I Deficiency

From the Departments of Internal Medicine (W.H., J.S., A.M., H.H., M.K., T.K., K.A.) and Biochemistry (K.M.), Fukuoka University School of Medicine, Fukuoka; and the Department of Internal Medicine, Oita Prefectural Hospital, Oita (H.N., K.Y.), Japan.

Correspondence to Jun Sasaki, MD, Department of Internal Medicine, School of Medicine, Fukuoka University, 45–1, 7-chome Nanakuma, Jonan-ku, Fukuoka 814–80, Japan. E-mail mm034505{at}msat.fukuoka-u.ac.jp

Abstract—We analyzed the genetic defect in a 67-year-old Japanese male patient with apolipoprotein (apo) A-I and high density lipoprotein (HDL) deficiencies, corneal opacities, and coronary artery disease. The plasma concentrations of apoA-I and HDL cholesterol were 2.9 to 7.3 mg/dL and 0.08 to 0.19 mmol/L, respectively. The lecithin:cholesterol acyltransferase (LCAT) activity and cholesterol esterification rate were <40% of normal control values. LCAT mass was 50% of normal control. Sequence analysis of polymerase chain reaction–amplified DNA of the proband's apoA-I gene showed a homozygous T-to-A transition resulting in the substitution of Val 156 with Glu (apoA-I Oita). Direct sequencing of samples obtained from other family members showed that the brother was homozygous, whereas the son was a heterozygous carrier of apoA-I Oita. The heterozygote for apo A-I Oita showed nearly 60% of normal apoA-I and normal HDL cholesterol levels. In vivo turnover studies in rabbits demonstrated that the variant apoA-I was rapidly cleared from plasma compared with normal human apoA-I. Our data suggest that the Val156Glu substitution is associated with apoA-I and HDL deficiency, partial LCAT deficiency, and corneal opacities and that Val156 of apoA-I may play an important role in apoA-I function.

Key Words: HDL deficiency • apolipoprotein variant • apoA-I Japanese • corneal opacities

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