Carbohydrate Deficient Glycoprotein Syndromes

描述（由申请人提供）：寡糖生物合成突变导致先天性糖基化障碍（CDG）。这一途径需要大量的基因来确保覆盖在每个细胞表面的蛋白质的正确糖基化。14种已知的CDG类型（原因）中的大多数是在过去4年内发现的。许多类型的CDG有待发现。目的1提出定义新类型CDG的基因、突变和分子基础。 CDG主要影响N-糖基化途径。我们现在已经确定了一组CDG患者的缺陷，在多种糖基化途径。其中有两个兄弟姐妹在一个称为COG（保守寡聚高尔基体）的异质8成员复合体中发生突变。COG组织一个有效的，有糖基化能力的高尔基体。在AIM 2中，我们将敲低每个COG亚基的细胞表达，以确定对聚糖生物合成以及对单个糖基转移酶和核苷酸糖转运蛋白的命运和功能定位的影响。这可能有助于识别其他类似的COG缺陷患者，并解释COG缺陷如何损害糖基化。这些目标的共同目标是解释这些突变如何导致糖基化病理学。从长远来看，我们希望了解新疾病的生理和分子基础，并为患者治疗提供基础。

DESCRIPTION (provided by applicant): Mutations in oligosaccharide biosynthesis cause Congenital Disorders of Glycosylation (CDG). This pathway requires scores of genes to insure proper glycosylation of proteins that cover the surface of every cell. Most of the 14 known types (causes) of CDG were discovered within the last 4 years. Many types of CDG await discovery. AIM 1 proposes to define the genes, mutations, and molecular basis of new types of CDG. CDG primarily affects the N-glycosylation pathway. We have now identified a group of CDG patients with defects in multiple glycosylation pathways. Among them are two siblings with mutations in a heterogeneous 8-member complex called COG (Conserved Oligomeric Golgi). COG organizes an efficient, glycosylation-competent Golgi. In AIM 2, we will knock down the cellular expression of each COG subunit to determine the effects on glycan biosynthesis and on the fate and functional localization of individual glycosyltransferases and nucleotide sugar transporters. This may help identify other similar COG-deficient patients and explain how COG deficiency compromises glycosylation. The common goal of these aims is to explain how these mutations cause glycosylation pathology. In the long run, we want to understand their physiological and molecular basis of new disorders and provide underpinnings for patient therapy.