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.