A novel homozygous missense mutation in the apo A-I gene with apo A-I deficiency.
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 550% 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.
Huang
W
W
Department of Internal Medicine, Fukuoka University School of Medicine, Japan.
Sasaki
J
J
Matsunaga
A
A
Nanimatsu
H
H
Moriyama
K
K
Han
H
H
Kugi
M
M
Koga
T
T
Yamaguchi
K
K
Arakawa
K
K
D000368:Aged; D000818:Animals; D016632:Apolipoprotein A-I / Q000172:deficiency* / Q000235:genetics*; D001053:Apolipoproteins / Q000097:blood; D001483:Base Sequence; D008076:Cholesterol, HDL / Q000097:blood / Q000172:deficiency; D004247:DNA / Q000235:genetics; D015180:Electrophoresis, Gel, Two-Dimensional; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D015151:Immunoblotting; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008297:Male; D009154:Mutation / Q000235:genetics*; D011817:Rabbits
D016632:Apolipoprotein A-I; D001053:Apolipoproteins; D008076:Cholesterol, HDL; D008055:Lipids; D008074:Lipoproteins; D004247:DNA