Pisciotta Livia, Calabresi Laura, Lupattelli Graziana, Siepi Donatella, Mannarino Massimo Raffaele, Moleri Elsa, Bellocchio Antonella, Cantafora Alfredo, Tarugi Patrizia, Calandra Sebastiano, Bertolini Stefano
Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, I-16132 Genoa, Italy.
Atherosclerosis. 2005 Sep;182(1):153-9. doi: 10.1016/j.atherosclerosis.2005.01.048. Epub 2005 Mar 31.
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.
我们研究了一个患有共显性单基因高胆固醇血症和低α脂蛋白血症的三代家族。先证者为一名48岁男性，被发现其低密度脂蛋白受体（LDL-R）基因存在先前报道的突变（IVS15-3 c>a），以及卵磷脂胆固醇酰基转移酶（LCAT）基因第6外显子的一个新突变（c.803 G>A），该突变导致非同义氨基酸替换（p.R244H）。这些突变在家族中独立分离。LDL-R突变与高水平的低密度脂蛋白胆固醇（LDL-C，6.20 - 9.85 mmol/L）和载脂蛋白B（apo B，170 - 255 mg/dL）相关，与先前报道的相同突变携带者的水平相当。LCAT突变与低水平的高密度脂蛋白胆固醇（HDL-C，0.67 - 0.80 mmol/L）和载脂蛋白A-I（apo A-I，96 - 110 mg/dL）相关。通过胆固醇酯化率（29 nmol/(mL/h)，而正常为30 - 60 nmol/(mL/h)）、LCAT活性（10 nmol/(mL/h)，而正常为20 - 55 nmol/(mL/h)）和LCAT质量（2.87 μg/mL，而正常为3.1 - 6.7 μg/mL）测定，先证者的LCAT功能降低。与非携带者家族成员相比，LCAT突变携带者的LCAT活性较低，且胆固醇酯化率（CER）和LCAT质量有降低趋势。在80名对照受试者和60名原发性低α脂蛋白血症患者中未发现LCAT突变。尽管脂蛋白谱不理想，但先证者仅具有轻度的动脉粥样硬化临床体征。这一意外发现可能是由于该患者在过去十年中一直在接受强化降脂治疗。
