MOLECULAR CHARACTERIZATION OF TWO PATIENTS WITH SEVERE LCAT DEFICIENCY

Lecithin:cholesterol acyltransferase (LCAT; EC2.3.1.43) is the major enzyme responsible for theesterification of cholesterol in circulating plasmalipoproteins. This is important in the human becauseunlike many other animal species, cholesterol exportedinto the plasma from the liver is largely unesterified.LCAT associates in plasma preferentially with thediscoidal apo A-I containing high-density lipoproteins(preb1-HDL), where it esterifies the free cholesterol(FC) using apo A-I as co-factor [1]. Through thisaction, LCAT plays a central role in both HDLmaturation to a-migrating spherical HDL and inreverse transport of cholesterol from peripheral tissuesto the liver, directly by interaction of the mature HDLwith the hepatic SR-BI receptor, or indirectly bytransfer of CE by cholesteryl ester transfer protein(CETP) to the VLDL and then LDL, much of which isultimately cleared by the liver via the LDL receptor [2].In addition, LCAT protein seems to have a scavengereffect toward LDL oxidation products, which isindependent of its cholesterol-esterifying activity [3].Mutations of LCAT (chr. 16q22.1, 6 exons) inhomozygous or compound heterozygous form cancause two major phenotypes: FLD (familial LCATdeficiency) and FED (Fish Eye Disease). Patients withFLD (OMIM No, 245900) have a complete loss ofboth a-LCAT activity (i.e. LCAT activity exerted onHDL) and b-LCAT activity (i.e. LCAT activity exertedon LDL), an increased proportion (>80%) of unesterifiedcholesterol in plasma. Clinical manifestationsgenerally include corneal opacification, anaemia andrenal disease with proteinuria, which progresses toterminal renal insufficiency. In FED (OMIM No.131620), there is partial loss of a-LCAT activity withnormal or slightly elevated FC in plasma and cornealopacification without renal disease [4,5]. Intermediatephenotypes have also been described. To date, morethan 60 mutations of LCAT have been identified [4–6];they involve all regions of the coding sequence andproduce a variety of defects, including normal secretionof LCAT with total loss of catalytic activity,reduced secretion with a partial or total loss ofcatalytic activity, secretion of an unstable or rapidlycatabolized enzyme, and complete degradation of theenzyme at its site of synthesis [4]. All subjects withFED or FLD have greatly reduced plasma HDLcholesterol concentrations (usually <0.3 mmol/l) andplasma levels of apo A-I below 50 mg/dl [6,7]; however,premature coronary artery disease is absent in mostFLD cases, but sometimes present, for unclear reasons,in some patients with FED [4,6,8]. We investigated twounrelated patients with clinical features of LCATdeficiency. Two of the three LCAT mutations foundin these patients were novel.