The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families.
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.


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-beta 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.


CONCLUSIONS
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.
Calabresi
Laura
L
Center E. Grossi Paoletti, Department of Pharmacological Sciences, University of Milano, 20133 Milan, Italy.
Pisciotta
Livia
L
Costantin
Anna
A
Frigerio
Ilaria
I
Eberini
Ivano
I
Alessandrini
Paola
P
Arca
Marcello
M
Bon
Gabriele Bittolo
GB
Boscutti
Giuliano
G
Busnach
Ghil
G
Frascà
Giovanni
G
Gesualdo
Loreto
L
Gigante
Maddalena
M
Lupattelli
Graziana
G
Montali
Anna
A
Pizzolitto
Stefano
S
Rabbone
Ivana
I
Rolleri
Marina
M
Ruotolo
Giacomo
G
Sampietro
Tiziana
T
Sessa
Adalberto
A
Vaudo
Gaetano
G
Cantafora
Alfredo
A
Veglia
Fabrizio
F
Calandra
Sebastiano
S
Bertolini
Stefano
S
Franceschini
Guido
G
D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000175:diagnosis / Q000235:genetics; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D003318:Corneal Opacity / Q000175:diagnosis / Q000235:genetics; D003937:Diagnosis, Differential; D004951:Esterification; D005192:Family Health; D005260:Female; D018628:Gene Dosage; D005838:Genotype; D006801:Humans; D007558:Italy; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000175:diagnosis* / Q000235:genetics*; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood / Q000235:genetics*; D014280:Triglycerides / Q000097:blood
D008074:Lipoproteins; D014280:Triglycerides; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase