CHOLESTEROL METABOLISM IN THE SMITH-LEMLI-OPITZ SYNDROME

Smith-Lemli-OPITZ 综合征中的胆固醇代谢

基本信息

批准号：
2403400
负责人：
G STEPHEN TINT
金额：
$ 17.54万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-05-01 至 1998-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2403400
关键词：
HMG coA reductases amniotic fluid blood chemistry child (0-11) cholanate compound cholesterol dietary lipid enzyme activity feces fibroblasts gene mutation genetic disorder genetic disorder diagnosis human subject laboratory rat lipid metabolism nutrition related tag oxidoreductase inhibitor postnatal growth disorder prenatal diagnosis prenatal growth disorder steroid biosynthesis syndrome tissue /cell culture urinalysis

HMG coA reductases amniotic fluid blood chemistry child (0-11) cholanate compound cholesterol dietary lipid enzyme activity feces fibroblasts gene mutation genetic disorder genetic disorder diagnosis human subject laboratory rat lipid metabolism nutrition related tag oxidoreductase inhibitor postnatal growth disorder prenatal diagnosis prenatal growth disorder steroid biosynthesis syndrome tissue /cell culture urinalysis

展开

项目摘要

Background; The Smith-Lemli-Opitz Syndrome (frequency ca 1:20,000) is a major public health problem which is described by a constellation of severe birth defects, including profound mental retardation and severe failure to thrive heretofore diagnosed only from its characteristic facies and limb and organ defects. We have recently reported, for the first time, a major biochemical defect in the syndrome. In 28 children plasma cholesterol levels (4 to 132 mg/dl) are below the fifth percentile for age matched controls while concentrations (6 to 61 mg/dl) of the cholesterol precursor 7-dehydrocholesterol (cholest-5,7-dien-3beta-ol) are elevated 2500 to 6000- fold above normal. Although not detected in controls, 7-dehydrocholesterol is also found in high concentrations in all tissues as well as in cultured fibroblasts. Abnormally low plasma cholesterol concentrations combined with high levels of 7-dehydrocholesterol demonstrate major block in cholesterol biosynthesis at the step in which the C-7,8 double bond of 7- dehydrocholesterol is reduced to form cholesterol. This may be sufficient to cause cholesterol deprivation in the embryo and fetus and prevent its proper development while the incorporation of 7-dehydrocholesterol in cells is likely to interfere with proper membrane function. We have also affected a prenatal diagnosis in two women by detecting elevated 7- dehydrocholesterol in amniotic fluid. An isotope incorporation assay in fibroblasts suggest that a test for carriers might be possible. Planned Studies: Our goals are to further define the biochemical defect in the syndrome by measurements of tissue lipids, by carrying out in vitro measurements of appropriate enzymes in the cholesterol biosynthetic pathway (3beta-hydroxy-delta 5.7-steroid delta7--reductase and HMG-CoA reductase) in affected, carrier and control fibroblasts cultured under various conditions and to examine cellular function and membrane properties under conditions of reduced C-7 reductase activity. An animal model of the disease is being developed and has already been used to plan and test treatment strategies and to further study the biochemistry of the disease. Four children have been placed on controlled high cholesterol diets (replacement therapy). As a results, their plasma cholesterol levels appeared to increase and they seem to progress a little more rapidly. Finally a collaborative effort is being planned to purify the C-7 reductase enzyme, sequence it and clone the cDNA. Eventually, it is hoped that an efficient test for carriers will be developed.

背景; Smith-Lemli-Opitz综合征（频率Ca 1：20,000）是一个主要的公共卫生问题，这是通过严重的星座来描述的出生缺陷，包括严重的智力低下和严重失败迄今为止，thrive仅从其特征相和肢体诊断出来和器官缺陷。我们最近首次报道了一个专业综合征的生化缺陷。在28个孩子中血浆胆固醇水平（4至132 mg/dl）低于年龄匹配的第五百分点对照，而胆固醇前体的浓度（6至61 mg/dL） 7-脱氢胆固醇（Cholest-5,7-Dien-3beta-Ol）的升高2500至6000- 折叠高于正常。尽管未在对照中检测到7-脱氢胆固醇在所有组织以及培养的所有组织中也有高浓度成纤维细胞。异常低血浆胆固醇浓度合并高水平的7-脱氢胆固醇在胆固醇生物合成在c-7,8双键为7-的步骤中脱氢胆固醇还原为形成胆固醇。这可能足够在胚胎和胎儿中引起胆固醇剥夺并防止其正确发育，而在细胞中掺入7-脱氢胆固醇可能会干扰适当的膜功能。我们也有通过检测升高的7-- 羊水中的脱氢胆固醇。同位素合并测定成纤维细胞表明可能可以进行载体测试。计划研究：我们的目标是进一步定义生化缺陷通过测量组织脂质的综合征，通过体外进行测量胆固醇生物合成途径中适当酶的测量（3beta-Hydroxy-delta 5.7-Syteroid Delta7-还原酶和HMG-COA还原酶）在受影响的，载体和控制的成纤维细胞中培养的成纤维细胞条件并检查细胞功能和膜特性 C-7还原酶活性降低的条件。一个动物模型疾病正在开发并已用于计划和测试治疗策略并进一步研究该疾病的生物化学。四个孩子被放置在受控的高胆固醇饮食上（替代疗法）。结果，它们的血浆胆固醇水平似乎增加了，它们似乎进步更快。最后，正在计划净化C-7还原酶酶，测序它并克隆cDNA。最终，希望将开发对载体的有效测试。