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Volume 146, Issue 1, Pages 141-151 (September 1999)


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Classical LCAT deficiency resulting from a novel homozygous dinucleotide deletion in exon 4 of the human lecithin: cholesterol acyltransferase gene causing a frameshift and stop codon at residue 144

Evelyn M. Teha, Jeffrey W. Chisholmb, Peter J. DolphinaCorresponding Author Informationemail address, Yves Pouliquenc, M. Savoldellic, J.L. de Gennese, Pascale Benliand

Received 28 September 1998; received in revised form 17 February 1999; accepted 23 February 1999. published online 16 August 2004.

Abstract 

Lecithin: cholesterolacyltransferase (LCAT) transacylates the fatty acid at the sn-2 position of lecithin to the 3β-OH group of cholesterol forming lysolecithin and the majority of cholesteryl ester found in plasma. LCAT participates in the reverse cholesterol transport pathway in man where it esterifies tissue-derived cholesterol following efflux from peripheral cells into HDL. Only 38 unique mutations in the human LCAT gene have been reported worldwide. Our French female proband presented with corneal opacity and no detectable plasma LCAT activity using either endogenous or exogenous assays. Her total plasma cholesterol and HDL cholesterol were low (2.34 mmol/l and 0.184 mmol/l, respectively) with a very high cholesterol/cholesteryl ester molar ratio (10.9:1). Plasma triglycerides were 0.470 mmol/l with low apo B (40.5 mg/dl), apo A-I (14.7 mg/dl), apo A-II (6.8 mg/dl) and apo E (2.1 mg/dl) levels. Plasma lipoprotein analysis by ultracentrifugation showed very low HDL concentrations and a characteristic shift of the lipoprotein profile towards larger, less dense particles. No proteinuria, renal dysfunction or signs of atherosclerosis were noted at age 45. Sequence analysis of her LCAT gene showed a novel homozygous TG-deletion at residues 138–139 that resulted in a frameshift causing the generation of a stop codon and premature termination of the LCAT protein at amino acid residue 144. Western blotting of the patient’s plasma using a polyclonal IgY primary antibody against human LCAT failed to demonstrate the presence of a truncated LCAT protein. A 53 bp mismatched PCR primer was designed to generate an Fsp 1 restriction site in the wild type sequence of exon 4 where the mutation occurred. The 155 bp PCR product from the wild type allele produced a 103 bp and 52 bp fragment with Fsp 1 and no cleavage products with the mutant allele thus permitting rapid screening for this novel mutation.

a The Lipoprotein Research Group, Department of Biochemistry and Molecular Biology, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, NS B3H 4H7, Canada

b The Department of Pathology, Wake Forest University School of Medicine, Medical Centre Boulevard, Winston Salem, NC 27157, USA

c Service d’Ophtalmologie, Hotel Dieu, Paris, France

d Laboratoire de Commun de Biologie Moléculaire, Hôpital Saint-Antoine, 184 rue du faubourg St.-Antoine, 75012 Paris, France

e Service d’Endocrinologie et Métabolisme, Hôpital de la Pitié, Paris, France

Corresponding Author InformationCorresponding author. Tel.: +1-902-4942439; fax: +1-902-4941355

PII: S0021-9150(99)00112-4


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