THE MOLECULAR PATHOLOGY OF LECITHIN - CHOLESTEROL ACYLTRANSFERASE (LCAT) DEFICIENCY SYNDROMES

Lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes repre sent a group of rare genetic disorders of HDL metabolism that have bee n the subject of a large number of clinical, biochemical, and genetic studies. Of special interest are patients with LCAT-related disorders with severe HDL deficiency and the apparent absence of premature ather osclerosis. This finding is inconsistent with the general concept that low HDL cholesterol levels are an obligate risk factor for atheroscle rosis. In this review, we describe 36 natural mutations in the LCAT ge ne that result in either familial LCAT deficiency (FLD) or the milder phenotype known as fish-eye disease (FED). We propose a new classifica tion of the natural mutations of the LCAT gene that are described to d ate. The defects are divided into-four classes based on both the clini cal and biochemical characterization of the patient and data that were obtained from the functional assessment of the mutant proteins. We de fine FLD-associated mutations that underlie a complete or nearly compl ete loss of LCAT activity due to null mutations (Class 1), and missens e mutations (Class 2), respectively. In addition, we distinguish two c lasses of FED-associated mutations (Classes 3,4) that underlie a parti al impairment of LCAT activity but differ in their lipoprotein substra te specificity. In addition, we review the evidence of atherosclerosis in subjects with LCAT deficiency syndromes. The observation that 6 (a ll males) of a total of 19 FED subjects suffered from premature CAD (a s defined by <55 years of age and <60 years of age for women and men, respectively) challenges the earlier assumption that the FED phenotype is not associated with increased risk of CAD. However, premature CAD remains an unusual clinical complication in FLD subjects.