METABOLISM AND GENETICS OF HYPOBETALIPOPROTEINEMIA

低β脂蛋白血症的代谢和遗传学

• 批准号: 2457250
• 负责人: GUSTAV SCHONFELD
• 金额: $ 30.83万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2457250
• 关键词: apolipoprotein B; autosomal dominant trait; clinical research; disease /disorder etiology; family genetics; genetic mapping; human subject; hypolipoproteinemia; linkage mapping; phenotype

DESCRIPTION: (Adapted from applicant's abstract): The goal of this research is to further understand the genetic basis of familial FHBL which is different from abetalipoproteinemia, due to MTP defects, or chylomicron retention disease. Currently FHBL is defined as an LDL cholesterol and/or apoB level below the 5th percentile, segregating as an autosomal dominant trait. The purpose of the proposed research is to identify the genes and genetic defects responsible for FHBL, including any new genes not heretofore associated with FHBL and to explain FHBL phenotypes by metabolic studies of apoB In some kindreds the FHBL phenotype is linked to the apoB gene. In a subgroup of such kindreds the molecular defects consist of truncation- producing mutations of the apoB gene. The investigators have identified ten different truncated forms of apoB cosegregating with the FHBL phenotype, and five other FHBL kindred in which no truncations are detectable, even with sensitive immunoblotting techniques. IN four of the latter kindreds the FHBL phenotype is linked to the apoB gene. In the fifth, the FHBL phenotype is not linked to the apoB gene; the molecular defects of apoB are not known in the four kindreds, not even the gene responsible is known for the fifth. The investigators plan to continue studies of the available kindreds and to identify more suitable kindreds in the St. Louis area, in Mexico and in Sicily, in collaboration with local investigators who were visiting scientists in the laboratory in St. Louis for the previous two to three years. The experimental approaches consist of linkage analysis using intragenic and flanky markers to test for linkage to the apoB gene and other candidate genes and genome searches, if necessary, to identify novel genes. For any detected linkages to known genes, the investigators plan to identify the gene defects. For any linkages detected as a result of the genome scans they plan to identify the genes and gene defects underlying the phenotypes. They also propose to perform in vivo metabolic studies to identify the physiologic bases of the low cholesterol/low apoB phenotypes. Of the four kindred that they wish to look at with FHBL in which the defect has been linked to the apoB gene, the largest is the D kindred which has seven affected subjects and sixteen unaffected subjects whom they have sampled. The C kindred has four affected subjects and five unaffected subjects whom they have sampled. The T kindred has eight affected subjects and seven unaffected subjects; and the fourth kindred, known as the Z kindred, has seven unaffected subjects whom they have sampled. In all these kindreds, transmission has been documented. The fifth family, kindred F, in which the defect has not been linked to the apoB gene, there are eleven affected family members, twenty-nine unaffected family members. In all these families it has been documented that the affected subjects do not have any evidence of truncated for of apoB.

描述：（改编自申请人摘要）：本研究的目标 研究目的是进一步了解家族性FHBL的遗传基础 由于MTP缺陷而不同于无β脂蛋白血症，或 乳糜微粒滞留病 目前FHBL被定义为低密度脂蛋白 胆固醇和/或载脂蛋白B水平低于第5百分位数，分离为 常染色体显性特征拟议研究的目的是 确定FHBL的基因和遗传缺陷，包括 任何迄今为止与FHBL无关的新基因， apoB代谢研究表型 在某些激酶中，FHBL表型与apoB基因连锁。 中 这种激酶的亚组的分子缺陷包括截断- 产生apoB基因的突变。 调查人员发现 与FHBL共分离的十种不同截短形式的apoB 表型，和其他五个FHBL家族，其中没有截短， 即使用灵敏的免疫印迹技术也能检测到。 四分之 后者使FHBL表型与apoB基因连锁。 在 第五，FHBL表型与apoB基因不连锁; apoB的分子缺陷在四种激酶中是未知的，甚至 负责第五个的基因是已知的。 研究人员计划继续研究现有的激酶， 在圣路易斯地区，在墨西哥， 在西西里，与当地调查人员合作， 圣路易斯实验室的科学家们在过去的两到三年里， 年 实验方法包括连锁分析， 基因内和侧翼标记以测试与apoB基因的连锁， 其他候选基因和基因组搜索，如有必要，以确定 新基因 对于任何检测到的与已知基因的联系， 研究人员计划确定基因缺陷。对于任何链接 作为基因组扫描的结果，他们计划识别基因， 以及表型背后的基因缺陷。 他们还建议， 进行体内代谢研究，以确定 低胆固醇/低载脂蛋白B表型。 在他们希望用FHBL观察的四个家族中， 缺陷已与apoB基因，最大的是D亲属 其中有7名受影响的受试者和16名未受影响的受试者， 他们已经采样。 C家族有四个受影响的主题和五个 未受影响的受试者，他们已经采样。 T家族有八个 受影响的受试者和七个未受影响的受试者;以及第四个亲属， 被称为Z家族，有七个未受影响的主题，他们有 抽检 在所有这些Kinetics，传输已被记录。 的 第五个家庭，亲属F，其中缺陷没有被链接到 apoB基因，有十一个受影响的家庭成员，二十九个 不受影响的家庭成员。 在所有这些家庭中， 受影响的受试者没有任何证据表明 apoB.