Molecular defect in familial lecithin:cholesterol acyltransferase (LCAT) deficiency: a single nucleotide insertion in LCAT gene causes a complete deficient type of the disease.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is a hereditary disorder with clinical manifestations including corneal opacity, premature atherosclerosis and renal failure. In this study, we analyzed the molecular base underlying a case of Japanese LCAT deficiency, in which both LCAT mass and activity of the proband were nearly absent. DNA blot hybridization analysis showed no gross rearrangement in the LCAT gene of the proband. The nucleotide sequence analysis of the cloned LCAT gene demonstrated only an extra nucleotide "C" insertion at the first exon, when compared to the sequence of wild type. This single base insertion caused a shift of the following reading frame, probably resulting in a truncated abnormal LCAT polypeptide that consist of only 16 amino acids. The direct sequence analysis of PCR-amplified DNA showed only the same insertion, indicating that the LCAT-deficient proband is a homozygote for the mutant allele. These results indicate that the clinical and biochemical feature of the patient is mainly caused by a complete deficiency of the enzyme based on a homozygous abnormality of LCAT gene.