A5007478590- Ion channel regulation and function
- Cardiac Ischemia and Reperfusion
- RNA modifications and cancer
- Genetics and Neurodevelopmental Disorders
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Genomics and Rare Diseases
- Genomic variations and chromosomal abnormalities
- Neurogenetic and Muscular Disorders Research
- CRISPR and Genetic Engineering
- DNA Repair Mechanisms
- Hedgehog Signaling Pathway Studies
- Genetic and Kidney Cyst Diseases
- Cardiac electrophysiology and arrhythmias
- Mitochondrial Function and Pathology
- Cancer-related gene regulation
- Ovarian cancer diagnosis and treatment
- Metabolism and Genetic Disorders
- Diet and metabolism studies
- Immunodeficiency and Autoimmune Disorders
- Pancreatic function and diabetes
- MicroRNA in disease regulation
- Congenital heart defects research
- RNA Research and Splicing
- Cardiac Arrest and Resuscitation
University Medical Center Utrecht
2016-2025
Heidelberg University
2019-2025
University Hospital Heidelberg
2019-2025
Wilhelmina Children's Hospital
2024
Utrecht University
2015-2024
Cancer Genomics Centre
2010-2021
Oncode Institute
2010-2021
Center for Molecular Medicine and Immunology
2017
University of Amsterdam
2015
Amsterdam UMC Location University of Amsterdam
2015
Protein misfolding and the formation of aggregates are increasingly recognized components pathology human genetic disease hallmarks many neurodegenerative disorders. As exemplified by polyglutamine diseases, propensity for protein is associated with length expansions age-dependent changes in protein-folding homeostasis, suggesting a critical role homeostatic buffer. To identify complement factors that protects cells against aggregates, we tested transgenic Caenorhabditis elegans strains...
An RNA interference (RNAi)-based genome-wide screen was performed to detect genes that contribute genome stability in somatic cells of Caenorhabditis elegans . We identified 61 such genes; these also affect spontaneous mutagenesis the germ line. Their sequence suggests a role DNA repair and/or replication, chromatin remodeling, or cell cycle control; there are many novel highly conserved from yeast human. Because known mutator causally involved hereditary and sporadic human cancers, it is...
Abstract Background The majority of mammalian genes contain multiple poly(A) sites in their 3' UTRs. Alternative cleavage and polyadenylation are emerging as an important layer gene regulation they generate transcript isoforms that differ UTRs, thereby modulating genes' response to UTR-mediated regulation. Enhanced at UTR proximal resulting global shortening was recently linked proliferation cancer. However, mechanisms regulate this enhanced alternative unknown. Results Here, we explored, on...
Objective. To determine the genotype–phenotype association in patients with adenosine deaminase-2 (ADA2) deficiency due to identical homozygous R169Q mutations CECR1.
Ketoacidosis is a potentially lethal condition caused by the imbalance between hepatic production and extrahepatic utilization of ketone bodies. We performed exome sequencing in patient with recurrent, severe ketoacidosis identified homozygous frameshift mutation gene encoding monocarboxylate transporter 1 (SLC16A1, also called MCT1). Genetic analysis 96 patients suspected having ketolytic defects yielded seven additional inactivating mutations MCT1, both heterozygous. Mutational status was...
ATP-sensitive potassium (KATP) channels, composed of inward-rectifying channel subunits (Kir6.1 and Kir6.2, encoded by KCNJ8 KCNJ11, respectively) regulatory sulfonylurea receptor (SUR1 SUR2, ABCC8 ABCC9, respectively), couple metabolism to excitability in multiple tissues. Mutations ABCC9 cause Cantú syndrome (CS), a distinct multiorgan disease, potentially via enhanced KATP activity. We screened an mutation-negative patient who also exhibited clinical hallmarks CS (hypertrichosis,...
Congenital diarrheal disorders are rare inherited intestinal characterized by intractable, sometimes life-threatening, diarrhea and nutrient malabsorption; some have been associated with mutations in diacylglycerol-acyltransferase 1 (DGAT1), which catalyzes formation of triacylglycerol from diacylglycerol acyl-CoA. We investigated the mechanisms DGAT1 deficiency contributes to failure using patient-derived organoids.We collected blood samples 10 patients, 6 unrelated pedigrees, who presented...
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...
Background Obesity is a global and severe health problem. Due to genetic heterogeneity, the identification of defects in patients with obesity can be time consuming costly. Therefore, we developed custom diagnostic targeted next-generation sequencing (NGS)-based analysis simultaneously identify mutations 52 obesity-related genes. The aim this study was assess yield approach suspected obesity. Methods DNA 1230 (median BMI adults 43.6 kg/m 2 ; median body mass index-SD children +3.4 SD)...
LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for Peutz-Jeghers hereditary cancer syndrome. It also somatically inactivated in approximately 30% non-small-cell lung (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines sensitive to MEK inhibitor CI-1040 shown by dose-dependent reduction proliferation rate, whereas LKB1 and KRAS alone do not confer similar sensitivity. We show this subset sensitised mTOR rapamycin....
Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, contribution genes located in this region to specific features remains uncertain. Among those, three genes, AKT3, HNRNPU ZBTB18 are highly expressed brain point mutations these have been recently identified children with neurodevelopmental phenotypes. In study, we...
ABSTRACT The zebrafish (Danio rerio) has become a popular vertebrate model organism to study organ formation and function due its optical clarity rapid embryonic development. use of genetically modified also allowed identification new putative therapeutic drugs. So far, most studies have relied on broad overexpression transgenes harboring patient-derived mutations or loss-of-function mutants, which incompletely the human disease allele in terms expression levels cell-type specificity...
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...
The structural maintenance of chromosomes (SMC) family proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in chromosome are linked rare breakage disorders. Here, we have identified a syndrome associated with severe lung disease early childhood. Four children from two unrelated kindreds died pulmonary during infancy following viral pneumonia evidence combined T B cell immunodeficiency. Whole exome sequencing revealed biallelic missense...