Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

Abstract

This article is available online at http://www.jlr.org frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be significantly associated with the disease. Furthermore, using structural analysis and modeling, the identifi ed APOE sequence changes were predicted to impact protein function. Abstract Autosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor ( LDLR ), APOB , and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADHassociated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR , 3.1% in APOB , and 1.7% in PCSK9 . We identifi ed 18 new variants in LDLR and 2 in PCSK9 . Three LDLR variants, including two newly identifi ed, were studied by minigene reporter assay confi rming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identifi ed in three patients with isolated severe hypercholesterolemia giving a

Таргетное Секвенирование У Больных С Клинически Диагностированным Наследственным Нарушением Липидного Обмена И Острым Коронарным Синдромом

“…В частности, у одного из них имелась вероятно патогенная ранее не описанная мутация p.Arg160His с локализацией в 4-м экзоне. Этот участок отвечает за связывание липопротеина APOE с ЛНПР, и уже известно об ассоциации вариантов данной локализации (с аналогичной аминокислотной заменой) с развитием аутосомно-доминантной семейной дисбеталипротеинемии [14]. Кроме того, у четверых пациентов имелся один и тот же полиморфизм гена APOE, отвечающий за образование атерогенной изоформы ε4 аполипопротеина Е (в одном из случаев одновременно с носительством мутации гена APOB неуточненной клинической значимости p.Ala4002Val).…”

Ethnicity and Response to Drug Therapy

“…Thus, the monogenic (Mendelian) form, often manifest as familial hypercholesterolemia (FH), is triggered by changes in a single gene. To date, the monogenic form has been linked primarily to mutations in three genes, the LDLR [10][11][12][13][14][15], proprotein convertase sublitisin/kexin type 9 (PCSK9) [16][17][18][19][20][21][22][23] and apolipoprotein B (APOB) genes [24][25][26][27][28]. In most cases, individuals with FH will have inherited one or both altered copies of the gene from affected parents.…”

“…This suggests that the same gene locus is involved in determining Lp(a) glycoprotein phenotypes and its plasma concentrations. Hence, variability in apolipoprotein genes related to the normal variance of lipoprotein concentrations play a major genetic role in multi-factorial forms of HL such as hTG, familial type III HL, polygenic HL [55] and ADH [24].…”

“…It has also been observed that some polymorphic gene locus controls the concentrations of Lp(a) lipoprotein complex in plasma which may vary very widely between individuals. Hence, variability in apolipoprotein genes related to the normal variance of lipoprotein concentrations play a major genetic role in multi-factorial forms of HL such as hTG, familial type III HL and polygenic HL [55], as well as ADH [24]. Furthermore, the effects of the APOE alleles on the phenotypic variance of plasma lipoprotein concentrations have been found to differ significantly among ethnic groups.…”

Variable phenotypic expression of nonsense mutation p.Thr5* in the APOE gene

“…These subjects may therefore actually not have a monogenic hypercholesterolemia or they may carry a mutation in another gene. One such gene could be the apolipoprotein E (APOE) gene where mutations p.Leu167del (c.500_502delTCC) [5], [6], [7] and p.Arg163Cys (c.487C > T) [8] recently have been found to cause autosomal dominant hypercholesterolemia.…”