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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059515-03
Application #
6139276
Study Section
Metabolism Study Section (MET)
Project Start
1998-01-01
Project End
2002-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
3
Fiscal Year
2000
Total Cost
$331,174
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Sherva, Richard; Yue, Pin; Schonfeld, Gustav et al. (2007) Evidence for a quantitative trait locus affecting low levels of apolipoprotein B and low density lipoprotein on chromosome 10 in Caucasian families. J Lipid Res 48:2632-9
Lin, Xiaobo; Chen, Zhouji; Yue, Pin et al. (2006) A targeted apoB38.9 mutation in mice is associated with reduced hepatic cholesterol synthesis and enhanced lipid peroxidation. Am J Physiol Gastrointest Liver Physiol 290:G1170-6
Lin, Xiaobo; Yue, Pin; Xie, Yan et al. (2005) Reduced intestinal fat absorptive capacity but enhanced susceptibility to diet-induced fatty liver in mice heterozygous for ApoB38.9 truncation. Am J Physiol Gastrointest Liver Physiol 289:G146-52
Schonfeld, G; Lin, X; Yue, P (2005) Familial hypobetalipoproteinemia: genetics and metabolism. Cell Mol Life Sci 62:1372-8
Lin, Xiaobo; Yue, Pin; Chen, Zhouji et al. (2005) Hepatic triglyceride contents are genetically determined in mice: results of a strain survey. Am J Physiol Gastrointest Liver Physiol 288:G1179-89
Yue, Pin; Tanoli, Tariq; Wilhelm, Olayinka et al. (2005) Absence of fatty liver in familial hypobetalipoproteinemia linked to chromosome 3p21. Metabolism 54:682-8
Garbow, J R; Lin, X; Sakata, N et al. (2004) In vivo MRS measurement of liver lipid levels in mice. J Lipid Res 45:1364-71
Tanoli, Tariq; Yue, Pin; Yablonskiy, Dmitriy et al. (2004) Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity. J Lipid Res 45:941-7
Chen, Zhouji; Fitzgerald, Robin L; Li, Gang et al. (2004) Hepatic secretion of apoB-100 is impaired in hypobetalipoproteinemic mice with an apoB-38.9-specifying allele. J Lipid Res 45:155-63
Schonfeld, Gustav (2003) Familial hypobetalipoproteinemia: a review. J Lipid Res 44:878-83

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