title: Characterization of a new LCAT mutation causing familial LCAT deficiency (FLD) and the role of APOE as a modifier gene of the FLD phenotype.
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.
authors.affiliation: Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal (IRCM), Montreal, QC, Canada. a.baass@umontreal.ca
authors.forename: Alexis
authors.initials: A
authors.lastname: Baass
authors.forename: Hanny
authors.initials: H
authors.lastname: Wassef
authors.forename: Michel
authors.initials: M
authors.lastname: Tremblay
authors.forename: Lise
authors.initials: L
authors.lastname: Bernier
authors.forename: Robert
authors.initials: R
authors.lastname: Dufour
authors.forename: Jean
authors.initials: J
authors.lastname: Davignon
mesh_terms: D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000097:blood; D053329:Apolipoprotein E2 / Q000097:blood / Q000235:genetics*; D001055:Apolipoproteins B / Q000097:blood; D015415:Biomarkers / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D002850:Chromatography, Gel; D004252:DNA Mutational Analysis; D004587:Electrophoresis, Agar Gel; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006952:Hyperlipoproteinemia Type III / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics*; D011792:Quebec; D012307:Risk Factors; D017384:Sequence Deletion; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D053329:Apolipoprotein E2; D001055:Apolipoproteins B; D015415:Biomarkers; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D014280:Triglycerides; D007862:Phosphatidylcholine-Sterol O-Acyltransferase