A5018204361- Cerebrovascular and genetic disorders
- Metalloenzymes and iron-sulfur proteins
- Moyamoya disease diagnosis and treatment
- Cell Adhesion Molecules Research
- Genomics and Rare Diseases
- Neurological diseases and metabolism
- Genetics and Neurodevelopmental Disorders
- Metabolism and Genetic Disorders
- S100 Proteins and Annexins
- Genomic variations and chromosomal abnormalities
- Neurological Disease Mechanisms and Treatments
- Protease and Inhibitor Mechanisms
- Intracerebral and Subarachnoid Hemorrhage Research
- Acute Ischemic Stroke Management
- Hormonal Regulation and Hypertension
- Cancer-related gene regulation
- Immunodeficiency and Autoimmune Disorders
- RNA Research and Splicing
- Advanced Proteomics Techniques and Applications
- Vitamin K Research Studies
- Neonatal Respiratory Health Research
- Protein Structure and Dynamics
- Tracheal and airway disorders
- Reconstructive Facial Surgery Techniques
- Amino Acid Enzymes and Metabolism
Leiden University Medical Center
2016-2025
University of Basel
2024
Leiden University
2021-2023
Ludwig-Maximilians-Universität München
2020
Amsterdam Neuroscience
2020
Amsterdam University Medical Centers
2020
Vrije Universiteit Amsterdam
2020
Indiana University – Purdue University Indianapolis
2020
Indiana University School of Medicine
2020
Delft University of Technology
2020
To determine the frequency of distinctive EGFr cysteine altering NOTCH3 mutations in 60,706 exomes exome aggregation consortium (ExAC) database.ExAC was queried for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), namely leading to a amino acid change one 34 domains NOTCH3. The genotype-phenotype correlation predicted by ExAC data tested an independent cohort Dutch CADASIL patients using quantified MRI lesions. registry probed...
PurposeCADASIL is a small-vessel disease caused by cysteine-altering pathogenic variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains NOTCH3 protein. We recently found that EGFr 7–34 have an unexpectedly high frequency general population (1:300). hypothesized more frequently cause much milder phenotype, thereby explaining important part CADASIL variability.MethodsAge at first stroke, survival and white matter hyperintensity volume were compared between 664 patients with...
<h3>Objective</h3> To determine the small vessel disease spectrum associated with cysteine-altering <i>NOTCH3</i> variants in community-dwelling individuals by analyzing clinical and neuroimaging features of UK Biobank participants harboring such variants. <h3>Methods</h3> The exome genome sequencing datasets (n = 50,000) cohorts cognitively healthy elderly 751) were queried for Brain MRIs scored according to Standards Reporting Vascular Changes on Neuroimaging criteria, information was...
Abstract Cysteine-altering missense variants (NOTCH3cys) in one of the 34 epidermal growth-factor-like repeat (EGFr) domains NOTCH3 protein are cause NOTCH3-associated small vessel disease (NOTCH3-SVD). NOTCH3-SVD is highly variable, ranging from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) at severe end spectrum to non-penetrance. The strongest known modifier NOTCH3cys variant position: located EGFr 1–6 associated a more phenotype than...
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL, is a hereditary cerebral small vessel disease caused by characteristic cysteine altering missense mutations in the NOTCH3 gene. CADASIL result an uneven number of residues one 34 epidermal growth factor like-repeat (EGFr) domains protein. The consequence unpaired residue EGFr domain increased multimerization tendency mutant NOTCH3, leading to toxic accumulation protein...
A retrospective study has shown that EGFr (epidermal growth factor-like repeat) group in the NOTCH3 gene is an important cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease modifier of age at first stroke white matter hyperintensity (WMH) volume. No yet assessed effect other known CADASIL modifiers, is, cardiovascular risk factors sex, context group. In this study, we determined relative disease-modifying effects group, sex factor on...
Abstract The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible impact clinical decision-making. Unbiased prospective studies quantify rES over routine genetic testing are, however, scarce. We performed a utility study compare conventional diagnostic workup with suspected disorders. In multicenter parallel cohort involving five Dutch NICUs, we in 60 disorder and monitored yield time diagnosis. To assess...
Abstract This study aims to inform future genetic reanalysis management by evaluating the yield of whole-exome sequencing (WES) in standard patient care Netherlands. Single-center data 159 patients with a neurodevelopmental disorder (NDD), which WES analysis and were performed between January 1, 2014, December 31, 2021, was retrospectively collected. Patients included if they under age 18 years at initial this did not result diagnosis. Demographic, phenotypic, genotypic characteristics...
Background and Purpose: Cysteine altering NOTCH3 variants, which have previously been exclusively associated with the rare hereditary small vessel disease cerebral autosomal dominant arteriopathy subcortical infarcts leukoencephalopathy, a population frequency of 1:300 worldwide. Using large database, taking genotype as starting point, we aimed to determine whether individuals harboring cysteine variant higher load markers on brain magnetic resonance imaging than controls, well risk stroke...
Abstract Aims CADASIL, the most prevalent hereditary cerebral small vessel disease, is caused by cysteine‐altering NOTCH3 variants ( cys ) leading to vascular protein aggregation. It has recently been shown that located in one of epidermal growth‐factor like repeat (EGFr) domains 1–6, are associated with a more severe phenotype than EGFr 7–34. The underlying mechanism for this genotype–phenotype correlation unknown. aim study was analyse whether variant position aggregation load. Methods We...
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by stereotyped missense mutations in NOTCH3. Whether these lead to the CADASIL phenotype via a neomorphic effect, or rather hypomorphic subject of debate. Here, we report two novel NOTCH3 mutations, both leading premature stop codon predicted loss function. The first mutation, c.307C>T, p.Arg103*, was detected brothers aged 50 55 years, brain MRI skin biopsy incompatible CADASIL....
Abstract Objective To validate whether serum Neurofilament Light‐chain (NfL) levels correlate with disease severity in CADASIL , and to determine NfL predicts progression survival. Methods Fourty‐one (pre‐) manifest individuals causing NOTCH 3 mutations 22 healthy controls were recruited from families. At baseline, MRI ‐lesion load clinical was determined stored. Disease measured 30/41 patients at 7‐year follow‐up, survival of all 17‐year follow‐up. Serum quantified using an ultra‐sensitive...
BACKGROUND: Chronic cerebellar lesions of presumed ischemic origin are frequently found in patients with stroke and as incidental findings. However, the differentiation embolic from caused by cerebral small vessel disease (SVD) is unclear. We aimed to investigate whether location chronic (deep versus cortical) indicates underlying cause (embolic SVD). METHODS: This study was a post hoc data analysis multinational ELAN trial (Early Versus Late Initiation Direct Oral Anticoagulants Patients...
Objective Vascular NOTCH3 protein ectodomain aggregation is a pathological hallmark of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), monogenic small vessel disease typically caused by cysteine‐altering variants in . Given their high population frequency, these are an important genetic contributor to stroke vascular dementia worldwide. Disease severity CADASIL highly variable mainly determined the position pathogenic variant ectodomain....
Abstract CADASIL is a NOTCH3 -associated cerebral small vessel disease. A pathological ultrastructural disease hallmark the presence of NOTCH3-protein containing deposits called granular osmiophilic material (GOM), in arteries. How these GOM develop over time and what their role progression largely unknown. Here, we studied humanized transgenic Arg182Cys mice, compared them to patient material, determined whether mice are associated with functional phenotype. We found that not static, but...
To determine whether extremely mild small vessel disease (SVD) phenotypes can occur in NOTCH3 variant carriers from Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) pedigrees using clinical, genetic, neuroimaging, skin biopsy findings.Individuals CADASIL fulfilling criteria for NOTCH3-associated SVD (mSVDNOTCH3) were selected the cross-sectional Dutch cohort (n=200), enrolled between 2017 2020. Brain magnetic resonance imaging...
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to toxic protein accumulation small- medium sized arterioles. The systemic but most pronounced brain vasculature where it leads clinical symptoms of recurrent stroke dementia. There no therapy for CADASIL, therapeutic development hampered lack feasible outcome measures biomarkers, both mouse models patients....
Disulfide bonds are an important class of protein post-translational modifications, yet this structurally crucial modification type is commonly overlooked in mass spectrometry (MS)-based proteomics approaches. Recently, the benefits online electrochemistry-assisted reduction S-S prior to MS analysis were exemplified by successful characterization disulfide peptides and small proteins. In current study, we have combined liquid chromatography (LC) with electrochemistry (EC) Fourier transform...