Carbohydrate Deficient Glycoprotein Syndromes

描述(申请人提供)：寡糖生物合成中的突变导致先天性糖基化紊乱(CDG)。这一途径需要数十个基因来确保覆盖在每个细胞表面的蛋白质适当的糖基化。在已知的14种CDG类型(病因)中，大多数是在过去4年内发现的。许多类型的CDG等待着人们的发现。目的1定义新型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患者存在多个糖基化途径的缺陷。其中有两个兄弟姐妹在一个称为COG(保守的寡聚体高尔基体)的异质8元复合体中发生了突变。COG组织了一个高效的、糖基化能力强的高尔基体。在AIM 2中，我们将下调COG各亚基的细胞表达，以确定其对糖生物合成的影响，以及对单个糖基转移酶和核苷酸糖转运体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缺乏症患者，并解释COG缺乏症如何影响糖基化。这些目标的共同目标是解释这些突变是如何导致糖基化病理的。从长远来看，我们希望了解它们在新疾病中的生理和分子基础，并为患者的治疗提供基础。

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.