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 (ape) A-I and high density lipoprotein (HDL) defic iencies, corneal opacities, and coronary artery disease. The plasma co ncentrations 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 acyltransfe rase (LCAT) activity and cholesterol esterification rate were <40% of normal control values. LCAT mass was approximate to 50% of normal cont rol. Sequence analysis of polymerase chain reaction-amplified DNA of t he proband's apoA-I gene showed a homozygous T-to-A transition resulti ng in the substitution of Val 156 with Glu (apoA-I Oita). Direct seque ncing of samples obtained from other family members showed that the br other was homozygous, whereas the son was a heterozygous carrier of ap oA-I Oita. The heterozygote for apo A-I Oita showed nearly 60% of norm al apoA-I and normal HDL cholesterol levels. In vivo turnover studies in rabbits demonstrated that the variant apoA-I was rapidly cleared fr om 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.