METABOLISM AND GENETICS OF HYPOBETALIPOPROTEINEMIA

低β脂蛋白血症的代谢和遗传学

• 批准号: 6343607
• 负责人: GUSTAV SCHONFELD
• 金额: $ 33.78万
• 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/6343607
• 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.

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