Witsch-Baumgartner M, Gruber M, Kraft H G, Rossi M, Clayton P, Giros M, Haas D, Kelley R I, Krajewska-Walasek M, Utermann G
Department of Medical Biology and Human Genetics, Innsbruck Medical University, Schöpfstrasse 41, 6020 Innsbruck, Austria.
J Med Genet. 2004 Aug;41(8):577-84. doi: 10.1136/jmg.2004.018085.
Smith-Lemli-Opitz syndrome (MIM 270400) is an autosomal recessive malformation and mental retardation syndrome that ranges in clinical severity from minimal dysmorphism and mild mental retardation to severe congenital anomalies and intrauterine death. Smith-Lemli-Opitz syndrome is caused by mutations in the Delta7 sterol-reductase gene (DHCR7; EC 1.3.1.21), which impair endogenous cholesterol biosynthesis and make the growing embryo dependent on exogenous (maternal) sources of cholesterol. We have investigated whether apolipoprotein E, a major component of the cholesterol transport system in human beings, is a modifier of the clinical severity of Smith-Lemli-Opitz syndrome.
Common apo E, DHCR7, and LDLR genotypes were determined in 137 biochemically characterised patients with Smith-Lemli-Opitz syndrome and 59 of their parents.
There was a significant correlation between patients' clinical severity scores and maternal apo E genotypes (p = 0.028) but not between severity scores and patients' or paternal apo E genotypes. In line with their effects on serum cholesterol levels, the maternal apo epsilon2 genotypes were associated with a severe Smith-Lemli-Opitz syndrome phenotype, whereas apo E genotypes without the epsilon2 allele were associated with a milder phenotype. The correlation of maternal apo E genotype with disease severity persisted after stratification for DHCR7 genotype. There was no association of Smith-Lemli-Opitz syndrome severity with LDLR gene variation.
These results suggest that the efficiency of cholesterol transport from the mother to the embryo is affected by the maternal apo E genotype and extend the role of apo E and its disease associations to modulation of embryonic development and malformations.
史密斯-勒米-奥皮茨综合征（MIM 270400）是一种常染色体隐性畸形和智力发育迟缓综合征，临床严重程度从轻微畸形和轻度智力发育迟缓到严重先天性异常和宫内死亡不等。史密斯-勒米-奥皮茨综合征由Delta7固醇还原酶基因（DHCR7；EC 1.3.1.21）突变引起，该突变损害内源性胆固醇生物合成，使发育中的胚胎依赖外源性（母体）胆固醇来源。我们研究了载脂蛋白E（人类胆固醇转运系统的主要成分）是否为史密斯-勒米-奥皮茨综合征临床严重程度的修饰因子。
对137例经生化特征鉴定的史密斯-勒米-奥皮茨综合征患者及其59名父母的常见载脂蛋白E、DHCR7和低密度脂蛋白受体（LDLR）基因型进行了测定。
患者的临床严重程度评分与母体载脂蛋白E基因型之间存在显著相关性（p = 0.028），但与患者或父体载脂蛋白E基因型之间无显著相关性。与它们对血清胆固醇水平的影响一致，母体载脂蛋白ε2基因型与严重的史密斯-勒米-奥皮茨综合征表型相关，而无ε2等位基因的载脂蛋白E基因型与较轻的表型相关。在按DHCR7基因型分层后，母体载脂蛋白E基因型与疾病严重程度的相关性依然存在。史密斯-勒米-奥皮茨综合征的严重程度与LDLR基因变异无关联。
这些结果表明，胆固醇从母体向胚胎转运的效率受母体载脂蛋白E基因型的影响，并将载脂蛋白E及其疾病关联的作用扩展至对胚胎发育和畸形的调节。
