Metabolism and Genetics of Hypobetalipoproteinemia

描述(由申请人提供)：这是一个竞争性更新申请，研究家族性低β-脂蛋白血症(FHBL)的遗传学和代谢。遗传学研究：除了我们的家系在染色体(CHR)2上有APOB突变外，我们还报道了7个FHBL连锁到染色体3p21上2 cM区域的家系。我们的目标之一是通过定位克隆，利用DHPLC(转基因波)技术和基因组DNA测序来检测突变，从而找到该区域的致病基因。第三组FHBL 5个家系与Chr2或3没有连锁。正在对这些家系进行全基因组基因分型。我们的第二个目标是进行连锁分析，以找到易感区域并最终找到基因(S)。代谢研究：使用磁共振波谱，我们发现携带apoB截断突变的FHBL受试者的肝脏脂肪是匹配对照组的5倍。我们还研究了极低密度脂蛋白-甘油三酯(TG)在这些受试者中的组装。静脉注射2H2-棕榈酸酯，用气相色谱-质谱法测定血浆和VLDL-甘油三酯中棕榈酸酯示踪剂/踪迹的比例，并对数据进行动力学模拟，结果表明FHBL受试者VLDL-TG来自肝脏的比例高于来自血浆棕榈酸酯的比例。肝脏脂肪(磁共振)与肝脏来源的贡献有显著的相关性(r=0.9，p=0.001)。我们的目标是将这些研究扩展到我们的FHBL受试者和患有代谢综合征X的患者，并评估代谢“风险因素”的重要性，如体重、胰岛素抵抗对这些群体中肝脏脂肪积累程度的影响。

DESCRIPTION (provided by applicant): This is a competitive renewal application to study the genetics and metabolism of familial hypobetalipoproteinemia (FHBL). Genetic studies: In addition to our families with APOB mutations on chromosome (chr) 2, we reported on seven families with linkage of FHBL to a 2cM region on chromosome 3p21. One of our aims is to find the etiologic gene in the region by positional cloning, using DHPLC (Transgenic Wave) technology and genomic DNA sequencing for mutation detection. A third group of FHBL five families manifests no linkage with either chr 2 or 3. Genomewide genotyping is being performed in these families. Our second aim is to perform linkage analyses to find susceptibility regions and ultimately the gene(s). Metabolic studies: Using magnetic resonance spectroscopy, we found 5-fold increases in liver fat in FHBL subjects bearing apoB truncation mutations compared with matched controls. We have also studied the assembly of VLDL-triglycerides (TG) in these subjects. Infusions of 2H2-palmitate, quantitation of palmitate tracer/tracee ratios in plasma and in VLDL-triglycerides by gas chromatography-mass spectrometry, and kinetic modeling of the data demonstrate that a greater proportion of VLDL-TG is derived from hepatic sources than from plasma palmitate in FHBL subjects than controls. A significant correlation was found between liver fat (by MRI) and the fractional contribution of hepatic sources (r=0.90, p=0.001). Our aim is to extend these studies in our FHBL subjects and to patients with the metabolic Syndrome X, and to evaluate the importance of metabolic "risk factors" such as body weight, insulin resistance on the extent of accumulation of liver fat in these groups.