Novel missense variants in LCAT and APOB genes in an Italian kindred with familial lecithin:cholesterol acyltransferase deficiency and hypobetalipoproteinemia

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• 作者：Paola Conca ; PhD^a ; Silvana Pileggi ; PhD^b ; Sara Simonelli ; PhD^a ; Emanuela Boer ; MD^c ; Giuliano Boscutti ; MD^c ; Lucia Magnolo ; PhD^d ; Patrizia Tarugi ; PhD^d ; Silvana Penco ; PhD^b ; Guido Franceschini ; PhD^a ; Laura Calabresi ; PhD^a ; ^{Laura.Calabresi@unimi.it} ; Monica Gomaraschi ; PhD^a
• 关键词：Apolipoprotein B ; Cholesterol esterification ; Familial hypobetalipoproteinemia ; Familial LCAT deficiency ; HDL subclasses ; High-density lipoproteins ; Lecithin ; cholesterol acyltransferase
• 刊名：Journal of Clinical Lipidology
• 出版年：2012
• 期刊代码：P92_19332874
• 类别：med
• 出版时间：May-June, 2012
• 卷：6
• 期：3
• 页码：244-250
• 文件大小：397 K

摘要

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Background

Lecithin:cholesterol acyltransferase (LCAT) is responsible for cholesterol esterification in plasma. Mutations of LCAT gene cause familial LCAT deficiency, a metabolic disorder characterized by hypoalphalipoproteinemia. Apolipoprotein B (apoB) is the main protein component of very-low-density lipoproteins and low-density lipoprotein (LDL). Mutations of APOB gene cause familial hypobetalipoproteinemia, a codominant disorder characterized by low plasma levels of LDL cholesterol and apoB.

Objective

This was a genetic and biochemical analysis of an Italian kindred with hypobetalipoproteinemia whose proband presented with hypoalphalipoproteinemia and severe chronic kidney disease.

Methods

Plasma lipids and apolipoproteins, cholesterol esterification, and high-density lipoprotein (HDL) subclass distribution were analyzed. LCAT and APOB genes were sequenced.

Results

The proband had severe impairment of plasma cholesterol esterification and high pre尾-HDL content. He was heterozygote for the novel LCAT P406L variant, as were two other family members. The proband鈥檚 wife and children presented with familial hypobetalipoproteinemia and were heterozygotes for the novel apoB H1401R variant. Cholesterol esterification rate of apoB H1401R carriers was reduced, likely attributable to the low amount of circulating LDL. After renal transplantation, proband鈥檚 lipid profile, HDL subclass distribution, and plasma cholesterol esterification were almost at normal levels, suggesting a mild contribution of the LCAT P406L variant to his pretransplantation severe hypoalphalipoproteinemia and impairment of plasma cholesterol esterification.

Conclusion

LCAT P406L variant had a mild effect on lipid profile, HDL subclass distribution, and plasma cholesterol esterification. ApoB H1401R variant was identified as possible cause of familial hypobetalipoproteinemia and resulted in a reduction of cholesterol esterification rate.