At the Laboratory for Molecular Diagnosis at the Center for Human Genetics, KU Leuven, Belgium, we focus on the systematic search for novel types of Congenital Disorders of Glycosylation (CDG) and their subsequent characterisation. CDG are a group of rare inborn errors of metabolism that lead to a broad range of clinical presentations such as intellectual disability, skeletal abnormalities and epilepsy. Our work covers both the fundamental and translational realms of science by helping us to understand the function of poorly understood genes and proteins and simultaneously providing a diagnosis to affected patients using state-of-the-art technology such as whole genome sequencing (WGS). At the Structural and Functional Glycobiology Unit (UGSF, UMR 8576) at the University of Lille, France, the focus is on understanding the impact of vesicular trafficking, and of manganese and calcium ER/Golgi homeostasis, on the regulation of the glycosylation process.
The position is opened in the context of a joint project co-hosted by KU Leuven and the University of Lille. It is expected that the successful candidate will spend approximately 24 months in each centre during the course of their 4-year PhD programme.
The identification and diagnosis of patients with Congenital Disorders of Glycosylation (CDG) is hampered by an extremely variable presentation ranging from single organ failure to complex disease with neurodevelopmental anddysmorphic features. Compounding this, there are also a huge number of genetically distinct CDG (>150 in total), many with only a few known cases. CDG are caused by mutations that affect the formation, trafficking or processing of glycans, leading to the aberrant glycosylation of proteins, this also makes the biochemical mechanisms leading to disease difficult to understand. Our laboratory has, for more than 20 years, been at the forefront of the identification of novel CDG. This includes the most common CDG subtype caused by mutations in PMM2 (Matthijs et al. 1997), and subsequently others such as COG1-CDG (Foulquier et al. 2007), COG4-CDG (Reynders etal. 2009), COG8-CDG (Foulquier et al. 2007) and MAN1B1-CDG (Rymen etal. 2013). Most recently, our focus has been upon CDG affecting the function of the oligosaccharyltransferase (OST) complex (Blommaert et al.2019).
The aim of this project will be to characterise novel CDG that have recently been identified in our lab through the screening of undiagnosed CDG patients using whole genome sequencing (WGS). This will be carried out using a variety of molecular biology techniques for the investigation of these defects in primary dermal fibroblasts derived from affected patients, as well as mammalian and fungal cell models. A successful candidate will also be trained in the analysis of WGS data from‘unsolved’ patients, in the hope of achieving diagnoses. This will include the application of state-of-the-art bioinformatics tools. The functional studies, including cell-biological, glycobiological and enzymatic experiments will be carried out under the supervision of Dr. François Foulquier, at the University of Lille.