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Characterization of a new LCAT mutation causing familial LCAT deficiency (FLD) and the role of APOE as a modifier gene of the FLD phenotype.

https://arctichealth.org/en/permalink/ahliterature150387
Source
Atherosclerosis. 2009 Dec;207(2):452-7
Publication Type
Article
Date
Dec-2009
Author
Alexis Baass
Hanny Wassef
Michel Tremblay
Lise Bernier
Robert Dufour
Jean Davignon
Author Affiliation
Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal (IRCM), Montreal, QC, Canada. a.baass@umontreal.ca
Source
Atherosclerosis. 2009 Dec;207(2):452-7
Date
Dec-2009
Language
English
Publication Type
Article
Keywords
Adult
Aged
Apolipoprotein A-I - blood
Apolipoprotein E2 - blood - genetics
Apolipoproteins B - blood
Biological Markers - blood
Cholesterol, HDL - blood
Cholesterol, LDL - blood
Chromatography, Gel
DNA Mutational Analysis
Electrophoresis, Agar Gel
Frameshift Mutation
Genetic Predisposition to Disease
Heterozygote
Homozygote
Humans
Hyperlipoproteinemia Type III - blood - enzymology - genetics
Lecithin Acyltransferase Deficiency - blood - enzymology - genetics
Male
Middle Aged
Pedigree
Phenotype
Phosphatidylcholine-Sterol O-Acyltransferase - genetics
Quebec
Risk factors
Sequence Deletion
Triglycerides - blood
Young Adult
Abstract
Familial LCAT deficiency (FLD) is a disease characterized by a defect in the enzyme lecithin:cholesterol acyltransferase (LCAT) resulting in low HDL-C, premature corneal opacities, anemia as well as proteinuria and renal failure. We have identified the first French Canadian kindred with familial LCAT deficiency. Two brothers, presenting classical signs of FLD, were shown to be homozygous for a novel LCAT mutation. This c.102delG mutation occurs at the codon for His35 and causes a frameshift that stops transcription at codon 61 abolishing LCAT enzymatic activity both in vivo and in vitro. It has a dramatic effect on the lipoprotein profile, with an important reduction of HDL-C in both heterozygotes (22%) and homozygotes (88%) and a significant decrease in LDL-C in heterozygotes (35%) as well as homozygotes (58%). Furthermore, the lipoprotein profile differs markedly between the two affected brothers who had different APOE genotypes. We propose that APOE could be an important modifier gene explaining heterogeneity in lipoprotein profiles observed among FLD patients. Our results suggest that a LCAT-/- genotype associated with an APOE epsilon2 allele could be a novel mechanism leading to dysbetalipoproteinemia.
PubMed ID
19515369 View in PubMed
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