Published online before print June 30, 2005, doi: 10.1161/01.ATV.0000175751.30616.13
© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
The Molecular Basis of Lecithin:Cholesterol Acyltransferase Deficiency Syndromes
A Comprehensive Study of Molecular and Biochemical Findings in 13 Unrelated Italian Families
From Center E. Grossi Paoletti (L.C., A.C., I.F., I.E., G.F.), Department of Pharmacological Sciences, University of Milano; Department of Internal Medicine (L.P., M.R., S.B.), University of Genova; Department of Internal Medicine (P.A., G.B.B.), S. Giovanni e Paolo Hospital, Venezia; Department of Clinical and Applied Medical Therapy (M.A., A.M.), University of Roma "La Sapienza"; Departments of Nephrology (G.B.) and of Pathology (S.P.), Santa Maria della Misericordia Hospital, Udine; Department of Nephrology, Dialysis, and Kidney Transplantation (G.B.), Niguarda Ca’ Granda Hospital, Milano; Nephrology Unit (G.F.), Ospedali Riuniti, Ancona; Department of Biomedical Sciences (L.G., M.G.), University of Foggia; Internal Medicine, Angiology, and Atherosclerosis (G.L., G.V.), Department of Clinical and Experimental Medicine, University of Perugia; Department of Pediatric Sciences (I.R.), University of Torino; San Raffaele Hospital (G.R.), Milano; Institute of Clinical Physiology (T.S.), CNR, Pisa; Department of Nephrology and Dialysis (A.S.), Vimercate Hospital; National Institute of Health (A.C.), Roma; Monzino Cardiologic Institute (F.V.), Milano; Department of Biomedical Sciences (S.C.), University of Modena and Reggio Emilia, Italy.
Correspondence to Guido Franceschini, Center E. Grossi Paoletti, Department of Pharmacological Sciences, Via Balzaretti 9, 20133 Milano, Italy. E-mail guido.franceschini{at}unimi.it
Objective— To better understand the role of lecithin:cholesterol acyltransferase (LCAT) in lipoprotein metabolism through the genetic and biochemical characterization of families carrying mutations in the LCAT gene.
Methods and Results— Thirteen families carrying 17 different mutations in the LCAT gene were identified by Lipid Clinics and Departments of Nephrology throughout Italy. DNA analysis of 82 family members identified 15 carriers of 2 mutant LCAT alleles, 11 with familial LCAT deficiency (FLD) and 4 with fish-eye disease (FED). Forty-four individuals carried 1 mutant LCAT allele, and 23 had a normal genotype. Plasma unesterified cholesterol, unesterified/total cholesterol ratio, triglycerides, very-low-density lipoprotein cholesterol, and pre-ß high-density lipoprotein (LDL) were elevated, and high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, apolipoprotein A-II, apolipoprotein B, LpA-I, LpA-I:A-II, cholesterol esterification rate, LCAT activity and concentration, and LDL and HDL3 particle size were reduced in a gene–dose-dependent manner in carriers of mutant LCAT alleles. No differences were found in the lipid/lipoprotein profile of FLD and FED cases, except for higher plasma unesterified cholesterol and unesterified/total cholesterol ratio in the former.
Conclusion— In a large series of subjects carrying mutations in the LCAT gene, the inheritance of a mutated LCAT genotype causes a gene–dose-dependent alteration in the plasma lipid/lipoprotein profile, which is remarkably similar between subjects classified as FLD or FED.
The impact of mutations in the LCAT gene on the plasma lipid/lipoprotein profile was investigated in 13 families carrying 17 different LCAT mutations. The inheritance of a mutated LCAT genotype causes a gene- dose-dependent alteration in the lipid/lipoprotein profile, which is remarkably similar between subjects classified as FLD or FED.
Key Words: familial lecithin:cholesterol acyltransferase deficiency • fish eye disease • high-density lipoproteins • lecithin:cholesterol acyltransferase • mutation
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