Research Jonathan Baets

Abstract

Spectrins are an integral part of the submembranous cytoskeleton providing both mechanical scaffolding and organization hub for other proteins in metazoan cells. The importance of spectrins to neuronal health is demonstrated by their association with a wide range of human neurological disorders (spectrinopathies). Currently, more than forty mutations in the gene encoding non-erythroid α-spectrin (SPTAN1) are associated with developmental and epileptic encephalopathies, hereditary motor neuropathy (HMN), spastic paraplegia (HSP), and ataxia. The underlying pathomechanisms remain largely unknown. In Drosophila, the highly conserved α-spec homolog similarly plays an important role in the nervous system development, as well as in synapse formation, its function and maintenance. Interestingly, synaptic defects associated with loss of α-spec can be suppressed via neuronal mitochondria repositioning. Conversely, increased levels of α-spec rescue a range of neuronal phenotypes linked to actin-dependent mitochondrial dysfunction in an α-synuclein neurodegeneration Drosophila model. These findings suggest that modulating the levels of α-spec in neurons might have an important and understudied impact on tuning mitochondrial dynamics and preserving neuronal health. Thus, the goal of my MSCA proposal is to deepen our knowledge on how neuronal actin and spectrin cytoskeleton regulate mitochondria and assess mitochondrial dysfunction at the basis of α-spectrinopathies, with a combined use of Drosophila as a model organism, and human iPSC-derived neurons as a platform to translate the findings to human neuronal health and disease. My project will provide insights on whether spectrin-associated mitochondrial dysfunction is a shared or specific feature for HMN, HSP and ataxia-associated spectrin mutants. I will deploy these findings to tailor a pharmacological treatment in the α-spectrinopathy neuronal cellular models and develop a therapeutic strategy

Researcher(s)

• Promoter: Baets Jonathan
• Fellow: Ermanoska Biljana

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Consumables budget in order to support the functioning of the IBB and the researchers associated with the UAntwerp who are affiliated or collaborate with the IBB, to be used to develop scientific activities.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Next Generation Sequencing technologies have accumulated genetic causes for Mendelian diseases, often without full insight into the cellular function of the gene involved. Conversely, patients with rare neurogenetic diseases are often lacking a genetic etiology. SPTAN1 (?-II-spectrin), a major cytoskeletal protein, is exemplary in this with a notably wide phenotypic spectrum but surprisingly little understanding of its molecular and cellular biology. Previously only associated with epilepsy and intellectual disability, we recently published novel mutations in SPTAN1 associated with Hereditary Motor Neuropathy and now also in Ataxia and Hereditary Spastic Paraplegia. ?-II-spectrin is the central component of the spectrin complex and is widely expressed in all cells but how its disturbances cause various neurological diseases is poorly understood. We will establish both cortical and motor neurons from patient-derived induced pluripotent stem-cells of three SPTAN1 mutations that are representative for the main associated diseases. Cytoskeletal abnormalities in these neurons will be studied using super-resolution microscopy, axonal transport assays and electrophysiological studies. Transcriptome-profiling of the neuronal cultures will allow to explore the interaction network of the spectrin complex. Ultimately, we will generate novel functional candidate genes that will be translated back to large genetic datasets of patients with diagnostically unresolved neurogenetic diseases.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Sporadic Inclusion Body Myositis (sIBM) is the most common myopathy above the age of 50 years and is presumed to be an acquired disorder. The interplay of potential mechanisms underlying sIBM pathogenesis remains unclear as is illustrated by a dual inflammatory-degenerative pathology in the affected muscle. Due to lack of effective therapy, steady decline of muscle strength results in loss of ambulation and ultimately reduced life expectancy. The uncertainty concerning the key pathomechanisms complicates the design of reliable experimental cell- or animal-models, emphasizing the relevance of well-designed experiments using human disease tissue. Capitalizing on the availability of patient disease-tissue under the form of diagnostic muscle biopsies, we established a unique (in house performed) high-resolution proteomics study, assessing the proteome of muscle lysates of 28 sIBM patients and 28 matched control individuals. This dataset provided unique insights in the proteomic landscape of sIBM, captivating known core features of sIBM pathomechanisms as well as highlighting strong signatures pointing towards selective failure of myogenesis. We identified KDM5A as a key upstream driver of sIBM pathology, interconnecting the DNA damage pathway, regulation of cell cycle and differentiation and energy homeostasis in sIBM skeletal muscle. The central aim of this project is to gather additional functional evidence that upregulation of KDM5A, a histone demethylase, is involved in sIBM pathomechanisms and failure of muscle regeneration in particular. Ultimately, the aim is working towards an actual therapy for sIBM, a currently untreatable and debilitating muscle disorder. Firstly, we will study KDM5A expression and activity and afterwards inhibition of KDM5A in immortalized human myoblast cell line with induced sIBM-like pathology. Secondly, we will study the effect of KDM5A overexpression in immortalized human myoblast cell lines from healthy middle-aged control individuals. Ultimately, we will establish immortalized patient-derived myoblasts from muscle as well as from induced Pluripotent Stem Cells (iPSC) and study the effect of KDM5A inhibition. This project could have major impact on the sIBM research field, by: 1) providing new mechanistic insights based on an alternative in vitro model not biased towards one of two general hypotheses; 2) resulting in a novel therapeutic strategy for sIBM. Furthermore, we aim to establish sIBM patient-derived immortalized myoblasts and iPSC differentiated into myotubes as a novel tools for further in vitro pathomechanistic and therapeutic studies.

Researcher(s)

• Promoter: Baets Jonathan
• Fellow: de Vries Geert

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Next Generation Sequencing (NGS) technologies have resulted in the accumulation of a large amount of genetic causes for Mendelian diseases, with often no clear-cut link or evident cellular function correlating to the phenotype available. Conversely, a multitude of patients with Rare Diseases, of which many suffer from neuropathies, are lacking a genetic etiology. SPTAN1 (?-II-spectrin) provides an excellent example of this, with a notably high phenotypical heterogeneity but surprisingly little known about its molecular biology and cellular functions. Previously only associated with epilepsy and intellectual disability, we recently published novel mutations in SPTAN1 associated with Hereditary Motor Neuropathy (HMN). Furthermore, our own unpublished data show patients with ataxia and Hereditary Spastic Paraplegia (HSP), widening the phenotypical spectrum even further. I set out to uncover the molecular causes of the phenotypical heterogeneity present in SPTAN1, starting with the curation of an extensive database of SPTAN1 mutations and their associated phenotypes. Leveraging the information contained in this database through the use of machine learning techniques, I will perform experiments in carefully chosen patient-derived induced Pluripotent Stem Cells (iPSCs) that will allow the uncovering of differential effects between variants in SPTAN1 and their associated phenotypes, yield novel candidate genes for such disorders and teach us about the patho-biology of spectrins.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

IMARK capitalizes on the deeply rooted expertise in biomedical imaging at the University of Antwerp to push the boundaries of precision medicine. By resolving molecular and structural patterns in space and time, IMARK aims at expediting biomarker discovery and development. To this end, it unites research groups with complementary knowledge and tools that cover all aspects of imaging-centred fundamental research, preclinical validation and clinical evaluation. IMARK harbours high-end infrastructure for electron and light microscopy, mass spectrometry imaging, magnetic resonance imaging, computed tomography, positron emission tomography and single-photon emission computed tomography. Moreover, IMARK members actively develop correlative approaches that involve multiple imaging modalities to enrich information content, and conceive dedicated image analysis pipelines to obtain robust, quantitative readouts. This unique blend of technologies places IMARK in an excellent position as preferential partner for public-private collaborations and offers strategic advantage for expanding the flourishing IP portfolio. The major application fields of the consortium are neuroscience and oncology. With partners from the Antwerp University Hospital and University Psychiatric Centre Duffel, there is direct access to patient data/samples and potential for translational studies.

Researcher(s)

• Promoter: De Vos Winnok
• Co-promoter: Baets Jonathan
• Co-promoter: Baggerman Geert
• Co-promoter: Bogers John-Paul
• Co-promoter: Keliris Georgios A.
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Mertens Inge
• Co-promoter: Morrens Manuel
• Co-promoter: Staelens Steven
• Co-promoter: Stroobants Sigrid
• Co-promoter: Timmerman Vincent
• Co-promoter: Timmermans Jean-Pierre
• Co-promoter: Verhaeghe Jeroen
• Co-promoter: Verhoye Marleen
• Fellow: Lanens Dirk
• Fellow: Prasad Aparna

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

Abstract

Next Generation Sequencing (NGS) technologies have resulted in the accumulation of a large amount of genetic causes for Mendelian diseases, with often no clear-cut link or evident cellular function correlating to the phenotype available. Conversely, a multitude of patients with Rare Diseases, of which many suffer from neuropathies, are lacking a genetic etiology. SPTAN1 (?-II-spectrin) provides an excellent example of this, with a notably high phenotypical heterogeneity but surprisingly little known about its molecular biology and cellular functions. Previously only associated with epilepsy and intellectual disability, we recently published novel mutations in SPTAN1 associated with Hereditary Motor Neuropathy (HMN). Furthermore, our own unpublished data show patients with ataxia and Hereditary Spastic Paraplegia (HSP), widening the phenotypical spectrum even further. I set out to uncover the molecular causes of the phenotypical heterogeneity present in SPTAN1, starting with the curation of an extensive database of SPTAN1 mutations and their associated phenotypes. Leveraging the information contained in this database through the use of machine learning techniques, I will perform experiments in carefully chosen patient-derived induced Pluripotent Stem Cells (iPSCs) that will allow the uncovering of differential effects between variants in SPTAN1 and their associated phenotypes, yield novel candidate genes for such disorders and teach us about the patho-biology of spectrins.

Researcher(s)

• Promoter: Baets Jonathan
• Co-promoter: Timmerman Vincent
• Fellow: Van de Vondel Liedewei

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Neuromuscular disorders (NMD) are diverse, usually inheriteddisorders that are chronically debilitating with tremendous societalimpact. We will focus on Hereditary Motor Neuropathies (HMN) andInherited/ Idiopathic Muscle Diseases (IMD). The unmet needs are"missing heritability" and lack of patho-mechanistic understandingand effective therapies. First, we will identify novel genetic causes ofHMN/IMD through advanced genetic studies in large patient cohortswithin international consortia. This allows the identification of rarecauses and unconventional mutation mechanisms. Secondly, basedon our recent identification of α-spectrin mutations in HMN we willstudy the associated spectrum of neuro-spectrinopathies. We willapply advanced machine learning techniques to a custom-builtdatabase featuring known and novel mutations. This will drivemutations modelling in patient derived induced pluripotent stem cellsin order to unravel the roles of the neuronal spectrin-cytoskeleton.Thirdly we will design novel therapies for idiopathic muscle disease,the most important being sporadic inclusion body myositis (sIBM).Using high-resolution proteomics techniques, we found that a keyupstream regulator driving the pathology is KDM5A, a histonedemethylase that induces failure of muscle regeneration in sIBMmuscle. We will use preclinical validation in cellular models to studytherapeutic KDM5A inhibition (pat. pend.) and will seek strategicindustry partners to develop this further.

Researcher(s)

• Promoter: Baets Jonathan
• Fellow: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Neuropathological research is an interdisciplinary field, in which imaging and image-guided interventions have become indispensable. However, the rapid proliferation of ever-more inquisitive technologies and the different scales at which they operate have created a bottleneck at the level of integration, a) of the diverse image data sets, and b) of multimodal image information with omics-based and clinical repositories. To meet a growing demand for holistic interpretation of multi-scale (molecule, cell, organ(oid), organism) and multi-layered (imaging, omics, chemo-physical) information on (dys)function of the central and peripheral nervous system, we have conceived μNEURO, a consortium comprising eight established teams with complementary expertise in neurology, biomedical and microscopic imaging, electrophysiology, functional genomics and advanced data analysis. The goal of μNEURO is to expedite neuropathological research and identify pathogenic mechanisms in neurodevelopmental and -degenerative disorders (e.g., Alzheimer's Disease, epilepsy, Charcot-Marie-Tooth disease) on a cell-to-organism wide scale. Processing large spatiotemporally resolved image data sets and cross-correlating multimodal images with targeted perturbations takes center stage. Furthermore, inclusion of (pre)clinical teams will accelerate translation to a clinical setting and allow scrutinizing clinical cases with animal and cellular models. As knowledge-hub for neuro-oriented image-omics, μNEURO will foster advances for the University and community including i) novel insights in molecular pathways of nervous system disorders; ii) novel tools and models that facilitate comprehensive experimentation and integrative analysis; iii) improved translational pipeline for discovery and validation of novel biomarkers and therapeutic compounds; iv) improved visibility, collaboration and international weight fueling competitive advantage for large multi-partner research projects.

Researcher(s)

• Promoter: Sijbers Jan
• Co-promoter: Baets Jonathan
• Co-promoter: Cras Patrick
• Co-promoter: De Vos Winnok
• Co-promoter: Giugliano Michele
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Staelens Steven
• Co-promoter: Stroobants Sigrid
• Co-promoter: Timmerman Vincent
• Co-promoter: Timmermans Jean-Pierre
• Co-promoter: Verhoye Marleen
• Co-promoter: Weckhuysen Sarah

Research team(s)

• Vision lab

Project type(s)

• Research Project

Abstract

Sporadic Inclusion Body Myositis (sIBM) is the most common myopathy above the age of 50 years and is presumed to be an acquired disorder. The interplay of potential mechanisms underlying sIBM pathogenesis remains unclear as is illustrated by a dual inflammatory-degenerative pathology in the affected muscle. Due to lack of effective therapy, steady decline of muscle strength results in loss of ambulation and ultimately reduced life expectancy. The uncertainty concerning the key pathomechanisms complicates the design of reliable experimental cell- or animal-models, emphasizing the relevance of well-designed experiments using human disease tissue. Capitalizing on the availability of patient disease-tissue under the form of diagnostic muscle biopsies, we established a unique (in house performed) high-resolution proteomics study, assessing the proteome of muscle lysates of 28 sIBM patients and 28 matched control individuals. This dataset provided unique insights in the proteomic landscape of sIBM, captivating known core features of sIBM pathomechanisms as well as highlighting strong signatures pointing towards selective failure of myogenesis. We identified KDM5A as a key upstream driver of sIBM pathology, interconnecting the DNA damage pathway, regulation of cell cycle and differentiation and energy homeostasis in sIBM skeletal muscle. The central aim of this project is to gather additional functional evidence that upregulation of KDM5A, a histone demethylase, is involved in sIBM pathomechanisms and failure of muscle regeneration in particular. Ultimately, the aim is working towards an actual therapy for sIBM, a currently untreatable and debilitating muscle disorder. Firstly, we will study KDM5A expression and activity and afterwards inhibition of KDM5A in immortalized human myoblast cell line with induced sIBM-like pathology. Secondly, we will study the effect of KDM5A overexpression in immortalized human myoblast cell lines from healthy middle-aged control individuals. Ultimately, we will establish immortalized patient-derived myoblasts from muscle as well as from induced Pluripotent Stem Cells (iPSC) and study the effect of KDM5A inhibition. This project could have major impact on the sIBM research field, by: 1) providing new mechanistic insights based on an alternative in vitro model not biased towards one of two general hypotheses; 2) resulting in a novel therapeutic strategy for sIBM. Furthermore, we aim to establish sIBM patient-derived immortalized myoblasts and iPSC differentiated into myotubes as a novel tools for further in vitro pathomechanistic and therapeutic studies.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

SPTAN1 (α-II-spectrin) is the sole α-spectrin subtype in the nervous system and has a critical function in neuronal development and homeostasis. Intriguingly, mutations in SPTAN1 display a strikingly high degree of phenotypical heterogeneity. Previously only associated with epilepsy and intellectual disability, we recently published novel mutations in SPTAN1 associated with Hereditary Motor Neuropathy (HMN). We now have additional preliminary evidence that implicates SPTAN1 variants in both ataxia, Hereditary Spastic Paraplegia (HSP) as well as myopathy, highlighting the relevance of SPTAN1 mutations in rare neurological and (neuro)muscular diseases. In this project we will investigate the novel link between SPTAN1 mutations and ataxia phenotypes by: (1) investigating one specific recurrent variant; (2) identifying additional pathogenic variants using a multiplex PCR screening method and; (3) using patient-derived cells to investigate a.o. mRNA and protein expression levels. Doing so we aim to establish ataxia as a novel phenotype within SPTAN1 related diseases and explore fundamental cellular characteristics of ataxia associated SPTAN1 mutations.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Unraveling genotype-phenotype correlations in diseases associated with SPTAN1 SPTAN1 (alpha-II-spectrin) plays an essential role in neuronal development and homeostasis, as it is the only alpha spectrin subtype present in the nervous system. Mutations in SPTAN1 were initially associated with a spectrum of epilepsy phenotypes. However, recent studies have shown that a wide variety of neurological phenotypes, including hereditary motor neuropathies, hereditary spastic paraplegia and possibly ataxia, can be attributed to mutations in SPTAN1. At present, there is no clear idea of ​​the underlying pathogenetic mechanism involved for each of the phenotypes, nor of the existence of other modifiers involved that influence this clinical heterogeneity. As such, this project aims to collect a large number of patients carrying SPTAN1 mutations and various phenotypes in order to unravel the common and specific mechanisms of diseases associated with SPTAN1. More specifically, a new analysis of the WES / WGS data available within the framework of international collaborations will be carried out in order to create a representative and uniform SPTAN1 catalog. Ultimately, patient-derived iPSC cell lines will be generated in the hope of uncovering the complex mechanisms underlying phenotypic heterogeneity. The bioinformatic, statistical and histological analysis of the SPTAN1 catalog will allow a better understanding of the different genotype-phenotype correlations, which will be very useful in determining the mutations to be best modeled in iPSC cell lines derived from the patient.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Next Generation Sequencing (NGS) technologies have resulted in the accumulation of a large amount of genetic causes for Mendelian diseases, with often no clear-cut link or evident cellular function correlating to the phenotype available. Conversely, a multitude of patients with Rare Diseases, of which many suffer from neuropathies, are lacking a genetic etiology. SPTAN1 (?-II-spectrin) provides an excellent example of this, with a notably high phenotypical heterogeneity but surprisingly little known about its molecular biology and cellular functions. Previously only associated with epilepsy and intellectual disability, we recently published novel mutations in SPTAN1 associated with Hereditary Motor Neuropathy (HMN). Furthermore, our own unpublished data show patients with ataxia and Hereditary Spastic Paraplegia (HSP), widening the phenotypical spectrum even further. I set out to uncover the molecular causes of the phenotypical heterogeneity present in SPTAN1, starting with the curation of an extensive database of SPTAN1 mutations and their associated phenotypes. Leveraging the information contained in this database through the use of machine learning techniques, I will perform experiments in carefully chosen patient-derived induced Pluripotent Stem Cells (iPSCs) that will allow the uncovering of differential effects between variants in SPTAN1 and their associated phenotypes, yield novel candidate genes for such disorders and teach us about the patho-biology of spectrins.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Sporadic Inclusion-Body Myositis (sIBM) is the most common myopathy in older adults and has a significant impact on the quality of life; no treatment exists to date. Histopathologically sIBM is characterized by degenerative as well as inflammatory features. In addition to this evident inflammation, striking similarities are observed between sIBM and neurodegenerative diseases. Alternative disease mechanism are suspected since sIBM has no classic genetic cause nor does it respond to immunosuppression as a "classic" inflammatory disorder would. Previously we have taken advantage of the availability of disease tissue due to diagnostic muscle biopsies. This allows 'proteomics' studies that capture the entire set of proteins in the diseased muscle and the key 'signatures' of the underlying mechanisms. A total of 61 muscle samples of sIBM-patients and controls were studied. Integrative data-analysis points towards three crucial disease pathways. These are involved in cell growth and repair, DNA damage response and inflammation-control. In the current project we will further study the role of these pathways by performing focused protein expression studies in muscle tissue and through the specific manipulation of these pathways in human-derived myoblast cell-lines in order to reproduce both sIBM pathology and proteomesignature. This novel cell system can be used as a disease model and will aid in the design of disease 'biomarkers' and therapies for sIBM.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

La myosite à inclusions sporadique (MIS), est la myopathie la plus fréquente après l'âge de 50 ans. MIS est une maladie intrigante de la musculature squelettique. Phénotypiquement, la maladie est caractérisé par une faiblesse progressive sélective des fléchisseurs des poignets et des doigts en du quadriceps. Une biopsie musculaire montre des infiltrats inflammatoires (la myosite) et des inclusion protéinique (des vacuoles dites 'bordées'). L'objectif du projet est de mieux comprendre les mécanismes pathophysiologiques de MIS afin de développer des 'biomarqeurs' diagnostiques et des stratégies thérapeutiques. Il y a des similarités frappantes entre MIS est les maladies neurodégénératives, notamment la présence dans les muscles atteintes d'au moins de 15 protéines caractéristiques de la maladie d'Alzheimer. Basé sur connaissance préalable, nous postulons que la cause fondamentale est une perturbation de l'homéostasie des protéines. Nous allons nous servir de l'avantage de l'accès direct au 'tissu de maladie' sous la forme des biopsies musculaire diagnostiques. Ça nous permet de réaliser une approche protéomique, dans laquelle l'ensemble complet des protéines est identifié. Actuellement, les tissus musculaires de 32 patients avec une diagnostique de MIS sont l'objet d'investigations. Nous nous préparons pour les expérimentes de validation sous forme western blot. La bourse serais utilisé pour financer ces expérimentes indispensables.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Neurogenetics Group

Project type(s)

• Research Project

Abstract

Inherited Peripheral Neuropathies (IPN) constitute a large and diverse group of disorders causing length-dependent neurodegeneration of axons in the peripheral nervous system (PNS). As many other neuromuscular disorders, IPN are chronic, debilitating and in some instances life-threatening conditions resulting in tremendous disease burden for patients and society. Affecting 1 in 2500 individuals, IPN share the challenges common to other 'rare disorders' namely substantial delays in diagnosis due to lack of reliable diagnostic tools; lack of specialized centres and standards for optimal patient care; lack of fundamental understanding of the mechanisms of disease and the absence of effective therapies. For three types of IPN (pure motor forms, pure sensory forms and congenital forms) the 'missing heritability' is as high as 70%. In this project we will start from biobanking of patients with the above-mentioned understudied types of IPN and we will systematically map out the phenotypic characteristics. In parallel, we will conduct large-scale genetic studies using next-generation sequencing techniques in these cohorts. By doing so we will tackle the existing knowledge gap in the genetic groundwork of PNS disease. This will evidently improve patient diagnosis but will at the same time significantly enlarge our understanding of the crucial mechanisms leading to axonal degeneration of the peripheral nervous system. Thirdly we aim to study the striking variability in disease severity of IPN through detailed genotype-phenotype correlation. Ultimately this will facilitate future studies designing reliable 'disease biomarkers' amenable for disease severity assessment on the one hand and the identification of novel targets for future therapeutic strategies on the other hand.

Researcher(s)

• Promoter: Baets Jonathan
• Fellow: Beijer Danique

Research team(s)

• Neurogenetics Group
• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Hereditary myopathies are a group of rare disorders affecting the skeletal muscles. Diagnosis is based on clinical findings, results of electromyography and MRI of muscles as well as the study of muscle biopsy. Although the spectrum of causal genes for these disorders is already broad many patients still do not have a precise diagnosis at this moment. In this project we will apply next-generation sequencing techniques in order to elucidate the genetic architecture of these disorders. We have selected 50 patients who currently do not have a genetic diagnosis for their myopathy. We will use these robust modern technologies to identify several novel genes for inherited myopathies. The goal is to improve molecular diagnostics in patients, deepen our insights in the underlying disease mechanisms and finally to designate targets for future therapeutic strategies.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Neurogenetics Group

Project type(s)

• Research Project

Abstract

Neuromuscular disorders (NMD) form a large and diverse group of usually genetic diseases affecting spinal cord, peripheral nerve, neuromuscular junction and muscle. Most NMD are 'rare disorders' affecting less than 1 in 2000 individuals but the estimated total of 5000-7000 rare disorders affect 30 million Europeans. Most NMD are chronic, debilitating and often life-threatening resulting in tremendous disease burden for patients and society. The common challenges in NMD are: substantial delays in diagnosis due to lack of reliable diagnostic tools; lack of specialized centres and standards for optimal patient care; lack of fundamental understanding of the mechanisms of disease and the absence of effective therapies. In this project we will focus on inherited disorders of the peripheral nerve and skeletal muscle. First we will conduct large-scale genetic studies to improve patient diagnosis and to increase our understanding of the crucial mechanisms leading to the disease. Secondly we aim to study the striking variability in disease severity of NMD and confront this with the study of patient-derived tissues such as skin and muscle biopsies. This will help in the design of reliable 'disease biomarkers' that can be used to predict severity of disease and can also serve as a tool to follow the response to experimental therapies. Lastly we will use patient derived tissues to help identifying novel targets and strategies for future therapy of NMD.

Researcher(s)

• Promoter: De Jonghe Peter
• Fellow: Baets Jonathan

Research team(s)

• Neurogenetics Group

Project type(s)

• Research Project

Abstract

Inherited peripheral neuropathies (IPN) are clinically and genetically diverse disorders occurring in 1 out of every 2500 individuals. IPN are characterized by progressive length-dependent axonal degeneration in the peripheral nervous system (PNS) resulting in gait difficulties due to pronounced distal muscle weakness and sensory loss. In the current research project we focus on a less characterized subgroup of IPN namely Hereditary Sensory and Autonomic Neuropathy (HSAN) that are known to have a broad genetic spectrum. Consequently, the vast majority of patients remain without a genetic diagnosis today. In addition, our understanding of the disease mechanisms underlying this specific axonal degeneration in the PNS remains very incomplete. In this project we will apply new whole-exome sequencing technologies to a cohort of 20 patients from 10 families with HSAN in order to make a major breakthrough in our insights of the genetic groundwork of axonal degeneration in the PNS. This study aims to identify several new causal genes for HSAN. By doing so we will improve genetic diagnosis in patients, shed new light on the pathomechanisms of PNS axonal degeneration and help delineating common pathways that will ultimately provide a point of action for future therapeutic strategies.

Researcher(s)

• Promoter: Baets Jonathan

Research team(s)

• Neurogenetics Group

Project type(s)

• Research Project

Abstract

Clinical, neuropathological and molecular genetic characterisation of axonal and intermediate hereditary neuropathies including Hereditary Motor and Sensory Neuropathy type II (HMSN II), Hereditary Motor Neuropathy (HMN) and Hereditary Sensory and Autonomic Neuropathy (HSAN) in order to make detailed genotype-phenotype correlations. These will be instrumental in the design of diagnostic guidelines and will help orient further genetic and cell-biological studies into the disease mechanisms underlying hereditary disorders of the peripheral nervous system.

Researcher(s)

• Promoter: De Jonghe Peter
• Fellow: Baets Jonathan

Research team(s)

• Neurogenetics Group

Project type(s)

• Research Project

Abstract

Clinical, neuropathological and molecular genetic characterisation of axonal and intermediate hereditary neuropathies including Hereditary Motor and Sensory Neuropathy type II (HMSN II), Hereditary Motor Neuropathy (HMN) and Hereditary Sensory and Autonomic Neuropathy (HSAN) in order to make detailed genotype-phenotype correlations. These will be instrumental in the design of diagnostic guidelines and will help orient further genetic and cell-biological studies into the disease mechanisms underlying hereditary disorders of the peripheral nervous system.

Researcher(s)

• Promoter: De Jonghe Peter
• Fellow: Baets Jonathan

Research team(s)

• Neurogenetics Group

Project type(s)

• Research Project

Abstract

Clinical, neuropathological and molecular genetic characterisation of axonal and intermediate hereditary neuropathies including Hereditary Motor and Sensory Neuropathy type II (HMSN II), Hereditary Motor Neuropathy (HMN) and Hereditary Sensory and Autonomic Neuropathy (HSAN) in order to make detailed genotype-phenotype correlations. These will be instrumental in the design of diagnostic guidelines and will help orient further genetic and cell-biological studies into the disease mechanisms underlying hereditary disorders of the peripheral nervous system.

Researcher(s)

• Promoter: De Jonghe Peter
• Co-promoter: Claeys Kristl
• Fellow: Baets Jonathan

Research team(s)

• Neurogenetics Group

Project type(s)

• Research Project