Metabolism and Genetics of Hypobetalipoproteinemia

描述（由申请人提供）：这是一个竞争性更新申请，旨在研究家族性低β脂蛋白血症（FHBL）的遗传学和代谢。基因研究：除了我们在染色体（chr）2上有APOB突变的家族外，我们还报道了7个与染色体3 p21上2cM区域连锁的FHBL家族。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测序进行突变检测，找到该地区的致病基因。第三组的FHBL五个家庭表现出没有任何连锁的chr 2或3。全基因组基因分型正在这些家庭中进行。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。代谢研究：使用磁共振波谱，我们发现携带apoB截短突变的FHBL受试者的肝脏脂肪比匹配的对照组增加了5倍。我们还研究了这些受试者中VLDL-甘油三酯（TG）的组装。输注2 H2-棕榈酸酯，通过气相色谱-质谱法定量血浆和VLDL-甘油三酯中棕榈酸酯示踪剂/示踪剂比率，以及数据的动力学建模表明，与对照组相比，FHBL受试者中来自肝脏来源的VLDL-TG比例高于来自血浆棕榈酸酯的VLDL-TG比例。肝脂肪（MRI）和肝源的贡献率之间存在显著相关性（r=0.90，p=0.001）。我们的目的是将这些研究扩展到我们的FHBL受试者和代谢综合征X患者，并评估代谢“危险因素”的重要性，如体重，胰岛素抵抗对这些人群中肝脏脂肪积累的程度。

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.