Projects
1. The role of the COL4A2 in cerebrovascular and aneurysmal disorders: a functional approach.
Intracranial aneurysms (IAs) are sac-like dilatations localized in the cerebral artery walls, due to weakening of the vessel wall. Each year 0.7-1.9% of IAs rupture and lead to subarachnoid hemorrhage (SAH). It has a fatal outcome in 35% of affected individuals, a 25% risk of death in the first 10 years after the SAH and permanent brain damage in two-thirds of survivors. Intracranial aneurysms have been described in genetic conditions, i.e., autosomal dominant polycystic kidney disease (ADPKD) or COL4A1- or COL4A2-related disorders, often affecting vascular smooth muscle cell or vascular basement membrane function, strongly suggests additional genetic risk factors for an IA aneurysm formation and rupture.
This project will functionally investigate the contribution of variants in COL4A2 to cerebrovascular and aortic aneurysmal pathology by 1) whole exome sequencing analysis of genetically unsolved patients with intracranial aneurysms, 2) the investigating the effect of COL4A2 variants on ER stress in patient fibroblasts with COL4A2 variants, and 3) establishing and characterizing a col4a2 zebrafish model based on a pathogenic col4a2 helical variant in order to model and functionally validate other col4a2 variants in a second stage.
Our findings will ultimately improve patient care by a better characterization of the phenotypic spectrum, a better interpretation of variants and the identification of potential therapeutic strategies.
PhD student: Zofia Szymkowiak
Promotors: Marije Meuwissen, Bart Loeys & Dorien Schepers
2. A transcriptome-driven approach for unraveling genetically determined brain malformations.
Malformations of cortical development (MCD) are a heterogenous group of brain malformations, which represent a significant burden for health care and society. Affected individuals suffer from epilepsy and varying degrees of intellectual and motor disability. Using current molecular techniques, over half of MCD cases remain unsolved.
We aim to establish of a gene-specific disease signature based on RNA-sequencing data that pinpoints the disease gene or pathway on which whole genome sequencing (WGS)-based variant analysis should be focused. The selected genes affect either the PI3K-AKT-mTOR pathway or microtubule dynamics, two major pathways involved in brain development. Furthermore, we aim to increase the diagnostic yield in MCD patients by integrating transcriptomics and WGS data of currently "unsolved" MCD cases, allowing the identification of additional variants of interest. Finally, we use the identified disease signatures in the validation of novel MCD candidate genes with similar pathophysiological mechanisms. The results of this project will guide the implementation of transcriptome analysis as another tool in the genetic diagnostic toolbox for MCD and hereby improve patient management and appropriate counseling of families.
PhD student: Jessica Rosenblum
Promotors: Anna Jansen & Marije Meuwissen
3. Autophagy dysregulation in cerebral palsy: a common mechanism?​
Cerebral palsy (CP) is the most frequent cause of motor impairment in children. For long, lack of oxygen at birth has been considered the main cause of CP. However, large population-based studies have shown it to play a role in only around 12% of CP patients, while genetic causes are increasingly demonstrated. To this day, these genetic causes are heterogeneous and common mechanisms of action remain largely unknown. In our research project, systematic genetic analyses in a large cohort of paediatric CP patients led to the identification of multiple genetic variants in genes linked to autophagy. Autophagy is an important biological process that breaks down dysfunctional cell components, facilitating homeostatic balance and reduced neurotoxicity crucial for cell survival in times of stress (e.g. during birth). To assess the exact role of autophagy in the development of CP, we perform different analyses on patient-derived skin fibroblasts. The results of this research may have direct consequences for patient care, leading to improved diagnostic strategies, genetic counseling and even new treatment options in the future.
PhD student: Liene Thys
Promotors: Marije Meuwissen, Berten Ceulemans, Diane Beysen & Katrien Janssens
4. Axonal transport defects as shared mechanism in cerebral palsy-related disorders – a functional approach.
Cerebral palsy (CP) comprises a group of non-progressive neurodevelopmental disorders characterized by motor impairment and often accompanied by intellectual disability, epilepsy, and sensory deficits. While historically attributed to birth asphyxia, recent genomic research has revealed that many CP cases have a genetic basis. This project focuses on mutations in the KIF1A, AP-4, and KLC4 genes, which converge on a shared defect in ATG9A trafficking, disrupting neuronal autophagy, an essential process for maintaining neuronal health and connectivity. Using patient-derived and genome-edited iPSC-based neuronal models, we will elucidate how impaired ATG9A transport affects neuronal morphology, synaptic function, and network activity. Multi-modal analyses including live-cell imaging, patch-clamp electrophysiology, and multi-electrode array recordings will identify cellular phenotypes linking defective intracellular transport to neuronal dysfunction. We will then test pharmacological compounds—Rapamycin, Carbamazepine, and Tubastatin A—that activate autophagy or enhance axonal transport, assessing their ability to restore neuronal and network function. This project represents the first integrative attempt to mechanistically unify genetically diverse forms of CP under a common pathway involving autophagy and vesicular transport defects. By bridging molecular and functional evidence across multiple genetic etiologies, it aims to shift the current paradigm of CP from perinatal hypoxia toward defined, targetable cellular mechanisms, laying the groundwork for precision medicine approaches for affected children.
Postdoctoral Researcher: Dr. Claudio Peter D'Incal
Promotors: Anna Jansen & Marije Meuwissen​