Combined monogenic hypercholesterolemia and hypoalphalipoproteinemia caused by mutations in LDL-R and LCAT genes.
We studied a three generation family with co-dominant monogenic hypercholesterolemia and hypoalphalipoproteinemia. The proband, a 48 year-old male, was found to be heterozygous for a previously reported mutation in LDL receptor (LDL-R) gene (IVS15-3 c>a) and a novel mutation in exon 6 of lecithin cholesterol acyltransferase (LCAT) gene (c.803 G>A) causing a non-synonymous amino acid substitution (p.R244H). These mutations segregated independently in the family. The LDL-R mutation was associated with high levels of LDL-C (6.20-9.85 mmol/L) and apo B (170-255 mg/dL), comparable to those previously reported in carriers of the same mutation. The LCAT mutation was associated with low levels of HDL-C (0.67-0.80 mmol/L) and apo A-I (96-110 mg/dL). The proband had reduced LCAT function, as measured by cholesterol esterification rate (29 nmol/(mL/h) versus 30-60 nmol/(mL/h)), LCAT activity (10 nmol/(mL/h) versus 20-55 nmol/(mL/h)) and LCAT mass (2.87 microg/mL versus 3.1-6.7 microg/mL). Carriers of LCAT mutation had lower LCAT activity and a tendency to reduced cholesterol esterification rate (CER) and LCAT mass as compared to non-carrier family members. The LCAT mutation was not found in 80 control subjects and 60 patients with primary hypoalphalipoproteinemia. Despite the unfavourable lipoprotein profile, the proband had only mild clinical signs of atherosclerosis. This unexpected finding is probably due to the intensive lipid lowering treatment the patient has been on over the last decade.
Pisciotta
Livia
L
Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, I-16132 Genoa, Italy.
Calabresi
Laura
L
Lupattelli
Graziana
G
Siepi
Donatella
D
Mannarino
Massimo Raffaele
MR
Moleri
Elsa
E
Bellocchio
Antonella
A
Cantafora
Alfredo
A
Tarugi
Patrizia
P
Calandra
Sebastiano
S
Bertolini
Stefano
S
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001057:Apolipoproteins E / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism; D003324:Coronary Artery Disease / Q000235:genetics*; D004951:Esterification; D005192:Family Health; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D013631:Tangier Disease / Q000235:genetics*
D001057:Apolipoproteins E; D008055:Lipids; D011973:Receptors, LDL; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D008071:Lipoprotein Lipase