H2020Индивидуална стипендия2020–2022

OST-CDG-omics · Untangling the pathophysiology of congenital disorders of glycosylation affecting the OST complex

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2020-07-01 → 2022-06-30
Финансиране от ЕС: 178 320 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Вродените нарушения на гликозилирането пречат на клетките да прикрепят захарни вериги към протеини и липиди, което нарушава тяхната функция и правилното им сгъване. Анализът на тези дефекти помага за поставяне на точна диагноза при пациенти и разбиране на механизмите на заболяванията.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Untangling the pathophysiology of congenital disorders of glycosylation affecting the OST complex

The OST-CDG-omics project was conceived in order to further investigate the cause of disease in patients with Congenital Disorders of Glycosylation (CDG). These are inborn errors of metabolism (IEM) that disrupt glycosylation. This is the process of attaching sugar chains, or glycans, to lipids and proteins as they are being made by the cell. Glycans are important for the eventual function of these proteins or lipids. For example, they may be required to fold a protein correctly, or to traffic it to the correct place within the cell. Over 150 genetically distinct types of CDG have been discovered, this number will likely grow; 2% of the human genome encodes proteins responsible for glycan processing or recognition. CDG cause an extraordinarily wide range of often multisystemic clinical presentations. ⁠ This makes diagnosis of CDG very difficult; it is still an under-diagnosed disorder, even in countries where screening for CDG is common. We have used state-of-the-art technology that allows us to thoroughly investigate the genetic code of affected patients who are known to have a CDG, but are yet to receive a genetic diagnosis. This, alongside expert cell biological analysis of the resulting glycosylation defect, has provided us with a number of breakthroughs involving the identification of new forms of CDG, or clarifying the disease mechanisms of existing CDG. These have helped undiagnosed patients to finally come to an end of their diagnostic odyssey, as well as provided fruitful further avenues of research for scientists in their quest to fully understand the process of glycosylation and its biological impacts.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Congenital disorders of glycosylation (CDG) are a group of over 100 inherited disorders characterised by defective glycosylation of proteins and lipids. Although the phenotypic and genetic characteristics of CDG as a whole are well established, their pathophysiology is poorly understood. In addition, the phenotype of affected patients is extremely variable, with dramatically different clinical presentations often appearing in patients with mutations in the same gene. I plan to investigate the link between pathogenic mutation and phenotype using recent advances in omics technologies, with a focus on the regulation of genes implicated in the pathophysiology of CDG.Firstly, using transcriptomics and epigenomics, I will identify the mechanism by which mutations in homologous genes encoding subunits of the oligosaccharyltransferase (OST) complex cause divergent phenotypes, thought to be due to differences in the regulation of tissue-specific transcription. The primary model for these studies will be the MAGT1 gene, mutations in which can lead to either a severe developmental disorder (MAGT1-CDG) or an isolated primary immune deficiency (XMEN). Secondly, using glycoproteomic techniques, I will study the proteins most affected by aberrant glycosylation in CDG affecting the OST, thereby characterising their pathophysiology in both patient-derived and modified cell lines. findings will be further investigated using targeted techniques such as LC-MS/MS. In summary, this study will simultaneously provide valuable insight into both the pathophysiology of CDG and the functional regulation of the OST complex, an understudied aspect of cell biology.

Оригинален текст от CORDIS (на английски).

Участници

KATHOLIEKE UNIVERSITEIT LEUVEN · LeuvenКоординаторБелгия