Publications by authors named "Robin van der Lee"

30 Publications

  • Page 1 of 1

Response to Biesecker et al.

Genet Med 2021 Apr 8;23(4):793-794. Epub 2021 Jan 8.

PerkinElmer Genomics, Duluth, GA, USA.

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http://dx.doi.org/10.1038/s41436-020-01055-zDOI Listing
April 2021

De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy.

Brain 2021 03;144(2):411-419

Dr. v. Hauner Children's Hospital, Department of Pediatric Neurology and Developmental Medicine, LMU - University of Munich, 80337, Germany.

Claudin-11, a tight junction protein, is indispensable in the formation of the radial component of myelin. Here, we report de novo stop-loss variants in the gene encoding claudin-11, CLDN11, in three unrelated individuals presenting with an early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Brain MRI showed a myelin deficit with a discrepancy between T1-weighted and T2-weighted images and some progress in myelination especially involving the central and peripheral white matter. Exome sequencing identified heterozygous stop-loss variants c.622T>C, p.(*208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Extended claudin-11 is predicted to form an alpha helix not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins. Our observations suggest that stop-loss variants in CLDN11 expand the genetically heterogeneous spectrum of hypomyelinating leukodystrophies.
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http://dx.doi.org/10.1093/brain/awaa410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940174PMC
March 2021

The role of clinical response to treatment in determining pathogenicity of genomic variants.

Genet Med 2021 Mar 22;23(3):581-585. Epub 2020 Oct 22.

PerkinElmer Genomics, Duluth, GA, USA.

Purpose: The 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants provide a framework to standardize terminology in the classification of variants uncovered through genetic testing. We aimed to assess the validity of utilizing clinical response to therapies specifically targeted to a suspected disease in clarifying variant pathogenicity.

Methods: Five families with disparate clinical presentations and different genetic diseases evaluated and treated in multiple diagnostic settings are summarized.

Results: Extended evaluations indicated possible genetic diagnoses and assigned candidate causal variants, but the cumulative clinical, biochemical, and molecular information in each instance was not completely consistent with the identified disease. Initiation of treatment specific to the suspected diagnoses in the affected individuals led to clinical improvement in all five families.

Conclusion: We propose that the effect of therapies that are specific and targeted to treatable genetic diseases embodies an in vivo physiological response and could be considered as additional criteria within the 2015 ACMG/AMP guidelines in determining genomic variant pathogenicity.
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http://dx.doi.org/10.1038/s41436-020-00996-9DOI Listing
March 2021

Deregulated Regulators: Disease-Causing cis Variants in Transcription Factor Genes.

Trends Genet 2020 07 22;36(7):523-539. Epub 2020 May 22.

Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, Department of Medical Genetics, The University of British Columbia, Vancouver, BC, Canada.. Electronic address:

Whole-genome sequencing is accelerating identification of noncoding variants that disrupt gene expression, although reports of such regulatory variants implicated in disease remain rare. A notable subset of described variants affect transcription factor (TF) genes and other master regulators in cis through dosage effects. From the literature, we compiled 46 regulatory variants linked to 40 TF genes implicated in rare diseases. We discuss the genomic geography of these variants and the evidence presented for their potential pathogenicity. To help advance research on candidate disease variants into the literature, we introduce an evidence framework specific to regulatory variants, which are under-represented in current variant classification guidelines. The clinical research interpretation of patient genomes may be advanced by considering regulatory variants, particularly those that deregulate TF genes.
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http://dx.doi.org/10.1016/j.tig.2020.04.006DOI Listing
July 2020

Ductus arteriosus and failed medical therapy.

J Neonatal Perinatal Med 2020 ;13(1):39-45

Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Pediatric Cardiology, Amsterdam, The Netherlands.

Background: Management of a patent ductus arteriosus (PDA) after pharmacological therapy failure in preterm neonates is controversial and shows marked practice variation. To evaluate which factors motivate the decision to ligate a PDA in clinical practice we examined several clinical and echocardiographic variables.

Methods: We conducted a retrospective single center cohort study. We included infants born at less than 37 weeks of gestation, admitted to our neonatal intensive care between 01.01.2008 and 31.12.2015 with a PDA detected on echocardiography after two or three courses of medical therapy. Logistic regression analyses were used to predict surgical ligation for twelve clinical and nine echocardiographic variables separately. We used the multiple imputation technique for missing values.

Results: A total of 89 neonates were included of which forty (45%), underwent surgical ligation of their PDA. In our final multivariate regression model, invasive respiratory support (OR 3.6, 95% CI 1.29-10.03), left atrial/aortic root ratio (OR 5.48, 95% CI 1.66-18.11) and presence of ductal steal (OR 3.82, 95% CI 1.47-9.91) were significant predictors for surgical ligation. The prediction model using clinical and echocardiographic variables explained 9% and 24% of the variability to ligate respectively, indicating significant residual variation due to unmeasured factors.

Conclusions: Our results indicate that invasive respiratory support, increased left atrial/aortic root ratio and the presence of ductal steal were important predictors for surgical ligation in our center. However, this explained only a small proportion of the variability, which emphasizes the need for evidence-based guidelines in the management of preterm neonates after failed pharmacological therapy for a PDA.
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http://dx.doi.org/10.3233/NPM-180152DOI Listing
February 2021

A Combined Mass Spectrometry and Data Integration Approach to Predict the Mitochondrial Poly(A) RNA Interacting Proteome.

Front Cell Dev Biol 2019 15;7:283. Epub 2019 Nov 15.

Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, Netherlands.

In order to synthesize the 13 oxidative phosphorylation proteins encoded by mammalian mtDNA, a large assortment of nuclear encoded proteins is required. These include mitoribosomal proteins and various RNA processing, modification and degradation enzymes. RNA crosslinking has been successfully applied to identify whole-cell poly(A) RNA-binding proteomes, but this method has not been adapted to identify mitochondrial poly(A) RNA-binding proteomes. Here we developed and compared two related methods that specifically enrich for mitochondrial poly(A) RNA-binding proteins and analyzed bound proteins using mass spectrometry. To obtain a catalog of the mitochondrial poly(A) RNA interacting proteome, we used Bayesian data integration to combine these two mitochondrial-enriched datasets as well as published whole-cell datasets of RNA-binding proteins with various online resources, such as mitochondrial localization from MitoCarta 2.0 and co-expression analyses. Our integrated analyses ranked the complete human proteome for the likelihood of mtRNA interaction. We show that at a specific, inclusive cut-off of the corrected false discovery rate (cFDR) of 69%, we improve the number of predicted proteins from 185 to 211 with our mass spectrometry data as input for the prediction instead of the published whole-cell datasets. The chosen cut-off determines the cFDR: the less proteins included, the lower the cFDR will be. For the top 100 proteins, inclusion of our data instead of the published whole-cell datasets improve the cFDR from 54% to 31%. We show that the mass spectrometry method most specific for mitochondrial RNA-binding proteins involves 4-thiouridine labeling followed by mitochondrial isolation with subsequent UV-crosslinking.
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http://dx.doi.org/10.3389/fcell.2019.00283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873792PMC
November 2019

JASPAR 2020: update of the open-access database of transcription factor binding profiles.

Nucleic Acids Res 2020 01;48(D1):D87-D92

Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway.

JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) for TFs across multiple species in six taxonomic groups. In this 8th release of JASPAR, the CORE collection has been expanded with 245 new PFMs (169 for vertebrates, 42 for plants, 17 for nematodes, 10 for insects, and 7 for fungi), and 156 PFMs were updated (125 for vertebrates, 28 for plants and 3 for insects). These new profiles represent an 18% expansion compared to the previous release. JASPAR 2020 comes with a novel collection of unvalidated TF-binding profiles for which our curators did not find orthogonal supporting evidence in the literature. This collection has a dedicated web form to engage the community in the curation of unvalidated TF-binding profiles. Moreover, we created a Q&A forum to ease the communication between the user community and JASPAR curators. Finally, we updated the genomic tracks, inference tool, and TF-binding profile similarity clusters. All the data is available through the JASPAR website, its associated RESTful API, and through the JASPAR2020 R/Bioconductor package.
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http://dx.doi.org/10.1093/nar/gkz1001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145627PMC
January 2020

Strabismus in Children With Intellectual Disability: Part of a Broader Motor Control Phenotype?

Pediatr Neurol 2019 11 11;100:87-91. Epub 2019 Apr 11.

Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; BC Children's Hospital and BC Women's Hospital, Vancouver, BC, Canada. Electronic address:

Purpose: Intellectual disability (ID) results from a heterogeneous group of disorders and affects 1% to 2% of children. ID frequently occurs in association with other clinical features such as seizures or malformations. We suspected that strabismus might also be unusually frequent in this population and that it might be associated with ID groups affecting motor control.

Methods: We reviewed phenotypic descriptors, extracted from medical records, for a heterogeneous series of 222 probands with ID who had been enrolled in a study of clinical application of exome sequencing. We estimated the frequency of strabismus and other common clinical features and explored statistical associations between them. Data from Population Data British Columbia and Online Mendelian Inheritance in Man were also examined for confirmation of our observations.

Results: Strabismus had a higher prevalence among probands with ID than in the general population (odds ratio = 5.46). Moreover, probands with both ID and strabismus were more likely to have problems affecting motor control than those with ID and no strabismus (odds ratio = 2.84). Hypotonia was one of the most common motor control subgroups affecting the ID probands, and a frequent co-occurrence of strabismus and hypotonia was also observed (odds ratio = 2.51) and supported by related gene literature review. There was no evidence for associations between strabismus and other frequent clinical features.

Conclusion: Strabismus is a frequent feature in individuals with ID. The frequent co-occurrence of strabismus and motor control phenotypes, in particular hypotonia, suggests that a common cerebellar mechanism or pathway may underlie these phenotypes.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.04.002DOI Listing
November 2019

Association between fetal sex, birthweight percentile and adverse pregnancy outcome.

Acta Obstet Gynecol Scand 2020 01 30;99(1):48-58. Epub 2019 Aug 30.

Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Introduction: The objective was to evaluate the association between fetal sex and adverse pregnancy outcome, while correcting for fetal growth and gestational age at delivery.

Material And Methods: Data from the Netherlands Perinatal Registry (1999-2010) were used. The study population comprised all white European women with a singleton delivery between 25 and 42  weeks of gestation. Fetuses with structural or chromosomal abnormalities were excluded. Outcomes were antepartum death, intrapartum/neonatal death (from onset of labor until 28 days after birth), perinatal death (antepartum death or intrapartum/neonatal death), a composite of neonatal morbidity (including infant respiratory distress syndrome, sepsis, necrotizing enterocolitis, meconium aspiration, persistent pulmonary hypertension of the newborn, periventricular leukomalacia, Apgar score <7 at 5 minutes, and intracranial hemorrhage) and a composite adverse neonatal outcome (perinatal death or neonatal morbidity). Outcomes were expressed stratified by birthweight percentile (p90 [large for gestation]) and gestational age at delivery (25 -27 , 28 -31 , 32 -36 , 37 -42 weeks). The association between fetal sex and outcome was assessed using the fetus at risk approach.

Results: We studied 1 742 831 pregnant women. We found no increased risk of antepartum, intrapartum/neonatal and perinatal death in normal weight and large-for-gestation males born after 28 weeks compared with females. We found an increased risk of antepartum death among small-for-gestation males born after 28 weeks (relative risk [RR] 1.16-1.40). All males born after 32  weeks of gestation suffered more neonatal morbidity than females regardless of birthweight percentile (RR 1.07-1.34). Infant respiratory distress syndrome, sepsis, persistent pulmonary hypertension of the newborn, Apgar score <7 at 5 minutes, and intracranial hemorrhage all occurred more often in males than in females.

Conclusions: Small-for-gestation males have an increased risk of antepartum death and all males born after 32  weeks of gestation have an increased risk of neonatal morbidity compared with females. In contrast to findings in previous studies we found no increased risk of antepartum, intrapartum/neonatal or perinatal death in normal weight and large-for-gestation males born after 28+0 weeks.
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http://dx.doi.org/10.1111/aogs.13709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973256PMC
January 2020

Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy.

Am J Hum Genet 2019 09 15;105(3):534-548. Epub 2019 Aug 15.

On behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands. Electronic address:

Early-infantile encephalopathies with epilepsy are devastating conditions mandating an accurate diagnosis to guide proper management. Whole-exome sequencing was used to investigate the disease etiology in four children from independent families with intellectual disability and epilepsy, revealing bi-allelic GOT2 mutations. In-depth metabolic studies in individual 1 showed low plasma serine, hypercitrullinemia, hyperlactatemia, and hyperammonemia. The epilepsy was serine and pyridoxine responsive. Functional consequences of observed mutations were tested by measuring enzyme activity and by cell and animal models. Zebrafish and mouse models were used to validate brain developmental and functional defects and to test therapeutic strategies. GOT2 encodes the mitochondrial glutamate oxaloacetate transaminase. GOT2 enzyme activity was deficient in fibroblasts with bi-allelic mutations. GOT2, a member of the malate-aspartate shuttle, plays an essential role in the intracellular NAD(H) redox balance. De novo serine biosynthesis was impaired in fibroblasts with GOT2 mutations and GOT2-knockout HEK293 cells. Correcting the highly oxidized cytosolic NAD-redox state by pyruvate supplementation restored serine biosynthesis in GOT2-deficient cells. Knockdown of got2a in zebrafish resulted in a brain developmental defect associated with seizure-like electroencephalography spikes, which could be rescued by supplying pyridoxine in embryo water. Both pyridoxine and serine synergistically rescued embryonic developmental defects in zebrafish got2a morphants. The two treated individuals reacted favorably to their treatment. Our data provide a mechanistic basis for the biochemical abnormalities in GOT2 deficiency that may also hold for other MAS defects.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732527PMC
September 2019

CiliaCarta: An integrated and validated compendium of ciliary genes.

PLoS One 2019 16;14(5):e0216705. Epub 2019 May 16.

Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, the Netherlands.

The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We generated independent experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins using multiple cell and animal model systems (mouse, zebrafish and nematode) and techniques. For example, we show that OSCP1, which has previously been implicated in two distinct non-ciliary processes, causes ciliogenic and ciliopathy-associated tissue phenotypes when depleted in zebrafish. The candidate list forms the basis of CiliaCarta, a comprehensive ciliary compendium covering 956 genes. The resource can be used to objectively prioritize candidate genes in whole exome or genome sequencing of ciliopathy patients and can be accessed at http://bioinformatics.bio.uu.nl/john/syscilia/ciliacarta/.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216705PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522010PMC
January 2020

Understanding the pathobiology in patent ductus arteriosus in prematurity-beyond prostaglandins and oxygen.

Pediatr Res 2019 07 9;86(1):28-38. Epub 2019 Apr 9.

Radboud Institute for Health Sciences, Amalia Children's Hospital, Division of Neonatology, Department of Pediatrics, Radboud university medical center, Geert Grooteplein zuid 10, Postal code 804, 6525 GA, Nijmegen, The Netherlands.

The ductus arteriosus (DA) is probably the most intriguing vessel in postnatal hemodynamic transition. DA patency in utero is an active state, in which prostaglandin E (PGE) and nitric monoxide (NO), play an important role. Since the DA gets programmed for postnatal closure as gestation advances, in preterm infants the DA frequently remains patent (PDA). PGE exposure programs functional postnatal closure by inducing gene expression of ion channels and phosphodiesterases and anatomical closure by inducing intimal thickening. Postnatally, oxygen inhibits potassium and activates calcium channels, which ultimately leads to a rise in intracellular calcium concentration consequently inducing phosphorylation of the myosin light chain and thereby vasoconstriction of the DA. Since ion channel expression is lower in preterm infants, oxygen induced functional vasoconstriction is attenuated in comparison with full term newborns. Furthermore, the preterm DA is more sensitive to both PGE and NO compared to the term DA pushing the balance toward less constriction. In this review we explain the physiology of DA patency in utero and subsequent postnatal functional closure. We will focus on the pathobiology of PDA in preterm infants and the (un)intended effect of antenatal exposure to medication on both fetal and neonatal DA vascular tone.
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http://dx.doi.org/10.1038/s41390-019-0387-7DOI Listing
July 2019

Curation and bioinformatic analysis of strabismus genes supports functional heterogeneity and proposes candidate genes with connections to RASopathies.

Gene 2019 May 15;697:213-226. Epub 2019 Feb 15.

Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Strabismus refers to the misalignment of the eyes and occurs in 2-4% of individuals. The low-resolution label "strabismus" covers a range of heterogeneous defects, which makes it challenging to unravel this condition. Consequently a coherent understanding of the causes is lacking. Here, we attempt to gain a better understanding of the underlying genetics by combining gene curation, diverse bioinformatic analyses (including gene ontology, pathway mapping, expression and network-based methods) and literature review. Through a phenotype-based curation process, we identify high-confidence and permissive sets of 54 and 233 genes potentially involved in strabismus. These genes can be grouped into 10 modules that together span a heterogeneous set of biological and molecular functions, and can be linked to clinical sub-phenotypes. Multiple lines of evidence associate retina and cerebellum biology with the strabismus genes. We further highlight a potential role of the Ras-MAPK pathway. Independently, sets of 11 genes and 15 loci tied to strabismus with definitive genetic basis have been compiled from the literature. We identify strabismus candidate genes for 5 of the 15 reported loci (CHD7; SLC9A6; COL18A1, COL6A2; FRY, BRCA2, SPG20; PARK2). Finally, we synthesize a Strabismus Candidate Gene Collection, which together with our curated gene sets will serve as a resource for future research. The results of this informatics study support the heterogeneity and complexity of strabismus and point to specific biological pathways and brain regions for future focus.
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http://dx.doi.org/10.1016/j.gene.2019.02.020DOI Listing
May 2019

The role of Neonatologist Performed Echocardiography in the assessment and management of neonatal shock.

Pediatr Res 2018 07;84(Suppl 1):57-67

Department of Neonatology, The Rotunda Hospital, Dublin, Ireland.

One of the major challenges of neonatal intensive care is the early detection and management of circulatory failure. Routine clinical assessment of the hemodynamic status of newborn infants is subjective and inaccurate, emphasizing the need for objective monitoring tools. An overview will be provided about the use of neonatologist-performed echocardiography (NPE) to assess cardiovascular compromise and guide hemodynamic management. Different techniques of central blood flow measurement, such as left and right ventricular output, superior vena cava flow, and descending aortic flow are reviewed focusing on methodology, validation, and available reference values. Recommendations are provided for individualized hemodynamic management guided by NPE.
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http://dx.doi.org/10.1038/s41390-018-0081-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257224PMC
July 2018

Probabilistic data integration identifies reliable gametocyte-specific proteins and transcripts in malaria parasites.

Sci Rep 2018 01 11;8(1):410. Epub 2018 Jan 11.

Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.

Plasmodium gametocytes are the sexual forms of the malaria parasite essential for transmission to mosquitoes. To better understand how gametocytes differ from asexual blood-stage parasites, we performed a systematic analysis of available 'omics data for P. falciparum and other Plasmodium species. 18 transcriptomic and proteomic data sets were evaluated for the presence of curated "gold standards" of 41 gametocyte-specific versus 46 non-gametocyte genes and integrated using Bayesian probabilities, resulting in gametocyte-specificity scores for all P. falciparum genes. To illustrate the utility of the gametocyte score, we explored newly predicted gametocyte-specific genes as potential biomarkers of gametocyte carriage and exposure. We analyzed the humoral immune response in field samples against 30 novel gametocyte-specific antigens and found five antigens to be differentially recognized by gametocyte carriers as compared to malaria-infected individuals without detectable gametocytes. We also validated the gametocyte-specificity of 15 identified gametocyte transcripts on culture material and samples from naturally infected individuals, resulting in eight transcripts that were >1000-fold higher expressed in gametocytes compared to asexual parasites and whose transcript abundance allowed gametocyte detection in naturally infected individuals. Our integrated genome-wide gametocyte-specificity scores provide a comprehensive resource to identify targets and monitor P. falciparum gametocytemia.
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http://dx.doi.org/10.1038/s41598-017-18840-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765010PMC
January 2018

JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework.

Nucleic Acids Res 2018 01;46(D1):D260-D266

Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway.

JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) and TF flexible models (TFFMs) for TFs across multiple species in six taxonomic groups. In the 2018 release of JASPAR, the CORE collection has been expanded with 322 new PFMs (60 for vertebrates and 262 for plants) and 33 PFMs were updated (24 for vertebrates, 8 for plants and 1 for insects). These new profiles represent a 30% expansion compared to the 2016 release. In addition, we have introduced 316 TFFMs (95 for vertebrates, 218 for plants and 3 for insects). This release incorporates clusters of similar PFMs in each taxon and each TF class per taxon. The JASPAR 2018 CORE vertebrate collection of PFMs was used to predict TF-binding sites in the human genome. The predictions are made available to the scientific community through a UCSC Genome Browser track data hub. Finally, this update comes with a new web framework with an interactive and responsive user-interface, along with new features. All the underlying data can be retrieved programmatically using a RESTful API and through the JASPAR 2018 R/Bioconductor package.
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http://dx.doi.org/10.1093/nar/gkx1126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753243PMC
January 2018

Genome-scale detection of positive selection in nine primates predicts human-virus evolutionary conflicts.

Nucleic Acids Res 2017 Oct;45(18):10634-10648

Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Hotspots of rapid genome evolution hold clues about human adaptation. We present a comparative analysis of nine whole-genome sequenced primates to identify high-confidence targets of positive selection. We find strong statistical evidence for positive selection in 331 protein-coding genes (3%), pinpointing 934 adaptively evolving codons (0.014%). Our new procedure is stringent and reveals substantial artefacts (20% of initial predictions) that have inflated previous estimates. The final 331 positively selected genes (PSG) are strongly enriched for innate and adaptive immunity, secreted and cell membrane proteins (e.g. pattern recognition, complement, cytokines, immune receptors, MHC, Siglecs). We also find evidence for positive selection in reproduction and chromosome segregation (e.g. centromere-associated CENPO, CENPT), apolipoproteins, smell/taste receptors and mitochondrial proteins. Focusing on the virus-host interaction, we retrieve most evolutionary conflicts known to influence antiviral activity (e.g. TRIM5, MAVS, SAMHD1, tetherin) and predict 70 novel cases through integration with virus-human interaction data. Protein structure analysis further identifies positive selection in the interaction interfaces between viruses and their cellular receptors (CD4-HIV; CD46-measles, adenoviruses; CD55-picornaviruses). Finally, primate PSG consistently show high sequence variation in human exomes, suggesting ongoing evolution. Our curated dataset of positive selection is a rich source for studying the genetics underlying human (antiviral) phenotypes. Procedures and data are available at https://github.com/robinvanderlee/positive-selection.
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http://dx.doi.org/10.1093/nar/gkx704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737536PMC
October 2017

PDE3 inhibition with enoximone as first-line therapy for severe persistent pulmonary hypertension of the newborn during neonatal transport: a case report.

Clin Case Rep 2017 Jan 23;5(1):18-21. Epub 2016 Nov 23.

Wilhelmina Childrens's Hospital University Medical Center Lundlaan 6 3584EA Utrecht Netherlands.

Severe Persistent pulmonary hypertension of the newborn (PPHN) can be effectively treated with a PDE3 inhibitor as first-line treatment during neonatal transport when iNO is not readily available. Starting iNO as soon as possible is strongly advised because of the complementary actions of both therapeutics.
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http://dx.doi.org/10.1002/ccr3.748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224780PMC
January 2017

Immunologic defects in severe mucocutaneous HSV-2 infections: Response to IFN-γ therapy.

J Allergy Clin Immunol 2016 09 7;138(3):895-898. Epub 2016 Apr 7.

Department of Internal Medicine, and RadboudUMC Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2016.02.025DOI Listing
September 2016

TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome.

Nat Cell Biol 2016 Jan 23;18(1):122-31. Epub 2015 Nov 23.

School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

The transition zone (TZ) ciliary subcompartment is thought to control cilium composition and signalling by facilitating a protein diffusion barrier at the ciliary base. TZ defects cause ciliopathies such as Meckel-Gruber syndrome (MKS), nephronophthisis (NPHP) and Joubert syndrome (JBTS). However, the molecular composition and mechanisms underpinning TZ organization and barrier regulation are poorly understood. To uncover candidate TZ genes, we employed bioinformatics (coexpression and co-evolution) and identified TMEM107 as a TZ protein mutated in oral-facial-digital syndrome and JBTS patients. Mechanistic studies in Caenorhabditis elegans showed that TMEM-107 controls ciliary composition and functions redundantly with NPHP-4 to regulate cilium integrity, TZ docking and assembly of membrane to microtubule Y-link connectors. Furthermore, nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237). Finally, MKS module membrane proteins are immobile and super-resolution microscopy in worms and mammalian cells reveals periodic localizations within the TZ. This work expands the MKS module of ciliopathy-causing TZ proteins associated with diffusion barrier formation and provides insight into TZ subdomain architecture.
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http://dx.doi.org/10.1038/ncb3273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580800PMC
January 2016

Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response.

PLoS Comput Biol 2015 Oct 20;11(10):e1004553. Epub 2015 Oct 20.

Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.

The RIG-I-like receptor (RLR) pathway is essential for detecting cytosolic viral RNA to trigger the production of type I interferons (IFNα/β) that initiate an innate antiviral response. Through systematic assessment of a wide variety of genomics data, we discovered 10 molecular signatures of known RLR pathway components that collectively predict novel members. We demonstrate that RLR pathway genes, among others, tend to evolve rapidly, interact with viral proteins, contain a limited set of protein domains, are regulated by specific transcription factors, and form a tightly connected interaction network. Using a Bayesian approach to integrate these signatures, we propose likely novel RLR regulators. RNAi knockdown experiments revealed a high prediction accuracy, identifying 94 genes among 187 candidates tested (~50%) that affected viral RNA-induced production of IFNβ. The discovered antiviral regulators may participate in a wide range of processes that highlight the complexity of antiviral defense (e.g. MAP3K11, CDK11B, PSMA3, TRIM14, HSPA9B, CDC37, NUP98, G3BP1), and include uncharacterized factors (DDX17, C6orf58, C16orf57, PKN2, SNW1). Our validated RLR pathway list (http://rlr.cmbi.umcn.nl/), obtained using a combination of integrative genomics and experiments, is a new resource for innate antiviral immunity research.
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http://dx.doi.org/10.1371/journal.pcbi.1004553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618338PMC
October 2015

Transcriptome analysis of complex I-deficient patients reveals distinct expression programs for subunits and assembly factors of the oxidative phosphorylation system.

BMC Genomics 2015 Sep 15;16:691. Epub 2015 Sep 15.

Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, PO BOX 9101, 6500 HB, Nijmegen, The Netherlands.

Background: Transcriptional control of mitochondrial metabolism is essential for cellular function. A better understanding of this process will aid the elucidation of mitochondrial disorders, in particular of the many genetically unsolved cases of oxidative phosphorylation (OXPHOS) deficiency. Yet, to date only few studies have investigated nuclear gene regulation in the context of OXPHOS deficiency. In this study we performed RNA sequencing of two control and two complex I-deficient patient cell lines cultured in the presence of compounds that perturb mitochondrial metabolism: chloramphenicol, AICAR, or resveratrol. We combined this with a comprehensive analysis of mitochondrial and nuclear gene expression patterns, co-expression calculations and transcription factor binding sites.

Results: Our analyses show that subsets of mitochondrial OXPHOS genes respond opposingly to chloramphenicol and AICAR, whereas the response of nuclear OXPHOS genes is less consistent between cell lines and treatments. Across all samples nuclear OXPHOS genes have a significantly higher co-expression with each other than with other genes, including those encoding mitochondrial proteins. We found no evidence for complex-specific mRNA expression regulation: subunits of different OXPHOS complexes are similarly (co-)expressed and regulated by a common set of transcription factors. However, we did observe significant differences between the expression of nuclear genes for OXPHOS subunits versus assembly factors, suggesting divergent transcription programs. Furthermore, complex I co-expression calculations identified 684 genes with a likely role in OXPHOS biogenesis and function. Analysis of evolutionarily conserved transcription factor binding sites in the promoters of these genes revealed almost all known OXPHOS regulators (including GABP, NRF1/2, SP1, YY1, E-box factors) and a set of novel candidates (ELK1, KLF7, SP4, EHF, ZNF143, and TEL2).

Conclusions: OXPHOS genes share an expression program distinct from other genes encoding mitochondrial proteins, indicative of targeted nuclear regulation of a mitochondrial sub-process. Within the subset of OXPHOS genes we established a difference in expression between mitochondrial and nuclear genes, and between nuclear genes encoding subunits and assembly factors. Most transcription regulators of genes that co-express with complex I are well-established factors for OXPHOS biogenesis. For the remaining six factors we here suggest for the first time a link with transcription regulation in OXPHOS deficiency.
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http://dx.doi.org/10.1186/s12864-015-1883-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570683PMC
September 2015

Feasibility of monitoring stress using skin conduction measurements during intubation of newborns.

Eur J Pediatr 2016 Feb 2;175(2):237-43. Epub 2015 Sep 2.

Princess Amalia Department of Paediatrics, Department of Neonatology, Isala Clinics, Dokter van Heesweg 2, 8025 AB, Zwolle, The Netherlands.

Unlabelled: The objective of this study was to assess the feasibility of monitoring stress responses in newborns during naso-tracheal intubation after two different premedication regimens, using skin conductance measurements (SCM). Twenty-two newborns were randomised and premedicated with morphine + vecuronium or propofol. SCM (peaks/s) were collected prior to, during and after the procedure. Threshold for interpreting responses as stressful was 0.21 peaks/s. Intubation conditions and physiological parameters were registered. Intubation conditions were good in all newborns. Administration of morphine (range 1.4-10.3 min) before administration of vecuronium did not affect SCM when a stressful stimulus was applied. Within 1.6 min (range 0.8-3 min) after administration of vecuronium, SCM disappeared in 10 of 11 newborns. Propofol reduced SCM in 10 of 11 newborns at the first attempt. Further attempts were associated with increasing SCM, mostly above a threshold of 0.21 peaks/s. There were no significant changes in physiological parameters during the procedure for either premedication regimen.

Conclusion: The variation in SCM between individual newborns limits the usefulness of SCM as stress monitor during intubation. The use of neuromuscular blockers for premedication precludes monitoring of SCM completely in newborns.

What Is Known: Skin conductance measurements have been used successfully to monitor pain in awake newborn infants.

What Is New: Premedicated newborns display significant interindividual variation in skin conductance measurements during an intubation procedure. Neuromuscular blockade causes skin conductance measurements to disappear completely.
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http://dx.doi.org/10.1007/s00431-015-2621-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724365PMC
February 2016

The RIG-I-like helicase receptor MDA5 (IFIH1) is involved in the host defense against Candida infections.

Eur J Clin Microbiol Infect Dis 2015 May 13;34(5):963-974. Epub 2015 Jan 13.

Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.

The induction of host defense against Candida species is initiated by recognition of the fungi by pattern recognition receptors and activation of downstream pathways that produce inflammatory mediators essential for infection clearance. In this study, we present complementary evidence based on transcriptome analysis, genetics, and immunological studies in knockout mice and humans that the cytosolic RIG-I-like receptor MDA5 (IFIH1) has an important role in the host defense against C. albicans. Firstly, IFIH1 expression in macrophages is specifically induced by invasive C. albicans hyphae, and patients suffering from chronic mucocutaneous candidiasis (CMC) express lower levels of MDA5 than healthy controls. Secondly, there is a strong association between missense variants in the IFIH1 gene (rs1990760 and rs3747517) and susceptibility to systemic Candida infections. Thirdly, cells from Mda5 knockout mice and human peripheral blood mononuclear cells (PBMCs) with different IFIH1 genotypes display an altered cytokine response to C. albicans. These data strongly suggest that MDA5 is involved in immune responses to Candida infection. As a receptor for viral RNA, MDA5 until now has been linked to antiviral host defense, but these novel studies show unexpected effects in antifungal immunity as well. Future studies are warranted to explore the potential of MDA5 as a novel target for immunotherapeutic strategies.
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http://dx.doi.org/10.1007/s10096-014-2309-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084092PMC
May 2015

Intrinsically disordered segments affect protein half-life in the cell and during evolution.

Cell Rep 2014 Sep 15;8(6):1832-1844. Epub 2014 Sep 15.

MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address:

Precise control of protein turnover is essential for cellular homeostasis. The ubiquitin-proteasome system is well established as a major regulator of protein degradation, but an understanding of how inherent structural features influence the lifetimes of proteins is lacking. We report that yeast, mouse, and human proteins with terminal or internal intrinsically disordered segments have significantly shorter half-lives than proteins without these features. The lengths of the disordered segments that affect protein half-life are compatible with the structure of the proteasome. Divergence in terminal and internal disordered segments in yeast proteins originating from gene duplication leads to significantly altered half-life. Many paralogs that are affected by such changes participate in signaling, where altered protein half-life will directly impact cellular processes and function. Thus, natural variation in the length and position of disordered segments may affect protein half-life and could serve as an underappreciated source of genetic variation with important phenotypic consequences.
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http://dx.doi.org/10.1016/j.celrep.2014.07.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358326PMC
September 2014

Intrinsically disordered proteins: regulation and disease.

Curr Opin Struct Biol 2011 Jun 20;21(3):432-40. Epub 2011 Apr 20.

MRC Laboratory of Molecular Biology, Hills Road, Cambridge, United Kingdom.

Intrinsically disordered proteins (IDPs) are enriched in signaling and regulatory functions because disordered segments permit interaction with several proteins and hence the re-use of the same protein in multiple pathways. Understanding IDP regulation is important because altered expression of IDPs is associated with many diseases. Recent studies show that IDPs are tightly regulated and that dosage-sensitive genes encode proteins with disordered segments. The tight regulation of IDPs may contribute to signaling fidelity by ensuring that IDPs are available in appropriate amounts and not present longer than needed. The altered availability of IDPs may result in sequestration of proteins through non-functional interactions involving disordered segments (i.e., molecular titration), thereby causing an imbalance in signaling pathways. We discuss the regulation of IDPs, address implications for signaling, disease and drug development, and outline directions for future research.
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http://dx.doi.org/10.1016/j.sbi.2011.03.011DOI Listing
June 2011

Morphine-induced muscle rigidity in a term neonate.

Ann Pharmacother 2009 Oct 15;43(10):1724-6. Epub 2009 Sep 15.

Department of Pediatric Surgery and Intensive Care, Erasmus MC Sophia Children's Hospital, Rotterdam, Netherlands.

Objective: To describe a potentially fatal adverse drug event after administration of morphine to a term neonate.

Case Summary: A 2-day-old term neonate experienced generalized muscle rigidity and laryngeal spasm resulting in acute respiratory failure on 2 separate occasions after morphine administration. The first occasion was after administration of bolus doses of fentanyl and morphine 100 microg/kg in the operating theater; administration of intravenous propofol 2 mg/kg resulted in relief of muscle rigidity. The second occasion occurred a few hours later, when the patient received a continuous infusion of morphine 4.4 microg/kg/h in the intensive care unit and experienced generalized muscle rigidity with respiratory compromise. The opioid antagonist naloxone 30 microg/kg was administered intravenously, which immediately resulted in a patent airway and spontaneous breathing. An objective causality assessment using the Naranjo probability scale revealed that the likelihood of morphine causing the patient's muscle rigidity on the second occasion was highly probable to definite. It is not clear whether the first occurrence of muscle rigidity was morphine-induced.

Discussion: We searched PubMed and EMBASE (through August 2009) for previous reports of morphine-related muscle rigidity and/or laryngeal spasm, using the search terms (muscle rigidity OR chest rigidity OR laryngeal spasm) AND (morphine OR fentanyl OR opioid). Sudden onset of muscle rigidity and laryngeal spasm is described in the literature as a rare but serious adverse event after infusion of fentanyl and similar opioids in both adults and young infants. However, there are no reports of this potentially fatal adverse event after administration of morphine. To our knowledge this is the first case reported of life-threatening muscle rigidity and laryngeal spasm after therapeutic doses of morphine in humans.

Conclusions: A serious adverse event consisting of generalized muscle rigidity and laryngospasm can occur after bolus administration of morphine as well as during continuous infusion. Clinicians should be aware of this possibility.
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http://dx.doi.org/10.1345/aph.1M268DOI Listing
October 2009