A5076498092- Metabolism and Genetic Disorders
- Erythrocyte Function and Pathophysiology
- Metabolomics and Mass Spectrometry Studies
- Hemoglobinopathies and Related Disorders
- Renal cell carcinoma treatment
- Mitochondrial Function and Pathology
- Folate and B Vitamins Research
- Amino Acid Enzymes and Metabolism
- Cancer, Hypoxia, and Metabolism
- Neonatal Health and Biochemistry
- RNA modifications and cancer
- Diet and metabolism studies
- Bladder and Urothelial Cancer Treatments
- Acute Myeloid Leukemia Research
- Cardiomyopathy and Myosin Studies
- Blood groups and transfusion
- Epigenetics and DNA Methylation
- Skin Protection and Aging
- Cancer Genomics and Diagnostics
- Genomics and Rare Diseases
- DNA Repair Mechanisms
- Hemoglobin structure and function
- Genetics and Neurodevelopmental Disorders
- bioluminescence and chemiluminescence research
- Genetic and Kidney Cyst Diseases
Utrecht University
2014-2025
University Medical Center Utrecht
2016-2025
Wilhelmina Children's Hospital
2013-2024
Heidelberg University
2021
University Hospital Heidelberg
2021
Boston Children's Hospital
2014
Howard Hughes Medical Institute
2006-2009
Johns Hopkins University
2008
Erasmus University Rotterdam
2006
University of California, Berkeley
2006
Amino acidopathies are a class of inborn errors metabolism (IEM) that can be diagnosed by analysis amino acids (AA) in plasma. Current strategies for AA include cation exchange HPLC with post-column ninhydrin derivatization, GC-MS, and LC-MS/MS-related methods. Major drawbacks the current methods time-consuming procedures, derivative problems, problems retention, MS-sensitivity. The use hydrophilic interaction liquid chromatography (HILIC) columns is an ideal separation mode compounds like...
Munc13 proteins are essential regulators of neurotransmitter release at nerve cell synapses. They mediate the priming step that renders synaptic vesicles fusion-competent, and their genetic elimination causes a complete block transmission. Here we have described patient displaying disorder characterized by dyskinetic movement disorder, developmental delay, autism. Using whole-exome sequencing, shown this condition is associated with rare, de novo Pro814Leu variant in major human paralog...
The malate-aspartate shuttle (MAS) is a redox that transports reducing equivalents across the inner mitochondrial membrane while recycling cytosolic NADH to NAD+. We genetically disrupted each MAS component generate panel of MAS-deficient HEK293 cell lines in which we performed [U-13C]-glucose tracing. cells have reduced serine biosynthesis, strongly correlates with lactate M+3/pyruvate M+3 ratio (reflective NAD+/NADH ratio), consistent NAD+ dependency phosphoglycerate dehydrogenase...
In many species, a dosage compensation complex (DCC) is targeted to X chromosomes of one sex equalize levels X-gene products between males (1X) and females (2X). Here we identify cis -acting regulatory elements that target the Caenorhabditis elegans chromosome for repression by DCC. The DCC binds discrete, dispersed sites on two types. rex (recruitment X) recruit in an autonomous, DNA sequence-dependent manner using 12-base-pair (bp) consensus motif enriched X. This critical binding,...
MDH2 encodes mitochondrial malate dehydrogenase (MDH), which is essential for the conversion of to oxaloacetate as part proper functioning Krebs cycle. We report bi-allelic pathogenic mutations in three unrelated subjects presenting with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate blood cerebrospinal fluid. Functional studies fibroblasts from affected showed both an apparently complete loss levels enzymatic activity close null. Metabolomics...
Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis which is poorly understood. When left untreated, disease can progress status epilepticus and death infancy. Here we present 12 previously undescribed patients six PLPBP. Suspected clinical diagnoses prior identification included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient)...
Abstract Phenotypic and biochemical categorization of humans with detrimental variants can provide valuable information on gene function. We illustrate this the identification two different homozygous resulting in enzymatic loss-of-function LDHD , encoding lactate dehydrogenase D, unrelated patients elevated D-lactate urinary excretion plasma concentrations. establish role by demonstrating that zebrafish results increased concentrations D-lactate. levels are rescued wildtype but not...
In metabolic diagnostics, there is an emerging need for a comprehensive test to acquire complete view of metabolite status. Here, we describe non-quantitative direct-infusion high-resolution mass spectrometry (DI-HRMS) based metabolomics method and evaluate the both dried blood spots (DBS) plasma. 110 DBS 42 patients harboring 23 different inborn errors metabolism (IEM) 86 plasma samples 38 21 IEM were analyzed using DI-HRMS. A peak calling pipeline developed in R programming language...
Mechanisms leading to osteoporosis are incompletely understood. Genetic disorders with skeletal fragility provide insight into metabolic pathways contributing bone strength. We evaluated 6 families rare phenotypes and by next-generation sequencing. In all the families, we identified a heterozygous variant in SGMS2, gene prominently expressed cortical encoding plasma membrane-resident sphingomyelin synthase SMS2. Four unrelated shared same nonsense variant, c.148C>T (p.Arg50*), whereas other...
Abstract Nodding syndrome is a neglected, disabling and potentially fatal epileptic disorder of unknown aetiology affecting thousands individuals mostly confined to Eastern sub-Saharan Africa. Previous studies have identified multiple associations—including Onchocerca volvulus, antileiomodin-1 antibodies, vitamin B6 deficiency measles virus infection—yet, none proven causal. We conducted case-control study children with early-stage nodding (symptom onset <1 year). Cases controls were...
Pain often persists in patients with an inflammatory disease, even when inflammation has subsided. The molecular mechanisms leading to this failure pain resolution and the transition chronic are poorly understood. Mitochondrial dysfunction sensory neurons links pain, but its role of is unclear. Transient causes neuronal plasticity, called hyperalgesic priming, which impairs induced by a subsequent stimulus. We identify that priming mice increases expression mitochondrial protein (ATPSc-KMT)...
Allergic diseases seem less prevalent in communities developed parts of the world, where parasite infections are highly prevalent. Altogether not much is known about association between chronic with tissue and blood-dwelling parasites atopy.In an area Gabon endemic for blood parasites, 520 schoolchildren were parasitologically examined skin prick-tested a set common environmental aeroallergens. Levels allergen-specific IgE polyclonal measured.In schistosome filarial increased age, whereas...
Abstract Lysosomes are implicated in a wide spectrum of human diseases including monogenic lysosomal storage disorders (LSDs), age-associated neurodegeneration and cancer. Profiling content using tag-based immunoprecipitation (LysoTagIP) cell animal models allowed major discoveries the field, however studying dysfunction patients remains challenging. Here, we report development “tagless LysoIP method” to enable rapid enrichment lysosomes, via immunoprecipitation, endogenous integral membrane...
The identification and understanding of the monogenic causes neurodevelopmental disorders are high importance for personalized treatment genetic counseling.To identify characterize novel genes a specific disorder characterized by refractory seizures, respiratory failure, brain abnormalities, death in neonatal period; describe outcome glutaminase deficiency humans; understand underlying pathological mechanisms.We performed exome sequencing cases without clear diagnosis, followed bioinformatic...