Peter Groenen - Academia.edu (original) (raw)

Papers by Peter Groenen

Chromosomale afwijkingen in dysmorfogenese. Een multidisciplinaire zoektocht naar de fundamentele processen tijdens onze embryonale ontwikkeling

Tijdschrift voor …, 1999

Abstract: Erfelijke of congenitale afwijkingen zijn onder te verdelen in diverse categorieën. Bij... more Abstract: Erfelijke of congenitale afwijkingen zijn onder te verdelen in diverse categorieën. Bij ongeveer 0, 6% van de nieuwgeborenen kunnen chromosomale afwijkingen worden vastgesteld. Deze afwijkingen kunnen wisselen van chromosoomduplicaties, volledige ...

GATA3 haplo-insufficiency causes human HDR syndrome

Nature, 2000

Terminal deletions of chromosome 10p result in a DiGeorge-like phenotype that includes hypoparath... more Terminal deletions of chromosome 10p result in a DiGeorge-like phenotype that includes hypoparathyroidism, heart defects, immune deficiency, deafness and renal malformations. Studies in patients with 10p deletions have defined two non-overlapping regions that contribute to this complex phenotype. These are the DiGeorge critical region II (refs 1, 2), which is located on 10p13-14, and the region for the hypoparathyroidism, sensorineural deafness, renal anomaly (HDR) syndrome (Mendelian Inheritance in Man number 146255), which is located more telomeric (10p14-10pter). We have performed deletion-mapping studies in two HDR patients, and here we define a critical 200-kilobase region which contains the GATA3 gene. This gene belongs to a family of zinc-finger transcription factors that are involved in vertebrate embryonic development. Investigation for GATA3 mutations in three other HDR probands identified one nonsense mutation and two intragenic deletions that predicted a loss of function, as confirmed by absence of DNA binding by the mutant GATA3 protein. These results show that GATA3 is essential in the embryonic development of the parathyroids, auditory system and kidneys, and indicate that other GATA family members may be involved in the aetiology of human malformations.

Genomics, 1998

the CDC5L rearrangement could not be demonstrated. ᭧ 1998 Academic Press Genetic studies have imp... more the CDC5L rearrangement could not be demonstrated. ᭧ 1998 Academic Press Genetic studies have implicated the short arm of chromosome 6 in congenital hydronephrosis. In previous studies, we described a fetus carrying a INTRODUCTION t(6;19)(p21;q13.1) as the sole cytogenetic anomaly and suffering from bilateral multicystic renal dysplasia Hereditary renal malformations constitute a major caused by a bilateral complete pelviureteric junction group of genetic disorders of which autosomal domiobstruction, resulting in a massive hydronephrosis.

Genomics, 1996

tion rather than the generation of a fusion gene as a possible underlying mechanism. ᭧ 1996 Acade... more tion rather than the generation of a fusion gene as a possible underlying mechanism. ᭧ 1996 Academic Press, Inc. The precise etiology of hydronephrosis caused by pelvi-ureteric junction obstruction is not yet known but there is convincing evidence for a genetic cause, with linkage analysis predicting a hereditary hydro-141

Biomarker-guided clinical development of the first-in-class anti-inflammatory FPR2/ALX agonist ACT-389949

British Journal of Clinical Pharmacology, 2016

The main objectives of these two phase I studies were to investigate safety and tolerability as w... more The main objectives of these two phase I studies were to investigate safety and tolerability as well as the pharmacokinetic/pharmacodynamic profile of the novel potent and selective formyl peptide receptor type 2 (FPR2)/Lipoxin A4 receptor (ALX) agonist ACT-389949. A challenge model was used to assess the drug&amp;amp;amp;amp;amp;#39;s anti-inflammatory potential, with the aim of selecting a dosing regimen for future patient studies. Two double-blind, randomized phase I studies investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of ACT-389949 at different doses and dosing regimens. Drug exposure was correlated with target engagement markers such as receptor internalization and cytokine measurements. The effect of FPR2/ALX agonism on neutrophil migration was studied in a lipopolysaccharide (LPS) inhalation model. ACT-389949 was well tolerated. Maximum concentrations were reached around 2 h after dosing, with a mean terminal half-life of 29.3 h [95% confidence interval (CI) 25.5, 33.7]. After multiple-dose administration, exposure increased by 111% (95% CI 89, 136), indicating drug accumulation. Administration of ACT-389949 resulted in a dose-dependent, long-lasting internalization of FPR2/ALX into leukocytes. Pro- and anti-inflammatory cytokines were dose-dependently but transiently upregulated only after the first dose. No pharmacological effect on neutrophil count was observed in the LPS challenge test performed at steady state. FPR2/ALX agonism with ACT-389949 was shown to be safe and well tolerated in healthy subjects. Receptor internalization and downstream mediators pointed towards a desensitization of the system, which may explain the lack of effect on neutrophil recruitment in the LPS challenge model.

Steroid and G Protein Binding Characteristics of the Seatrout and Human Progestin Membrane Receptor Alpha Subtypes and Their Evolutionary Origins

Endocrinology, 2006

A novel progestin receptor (mPR) with seven-transmembrane domains was recently discovered in spot... more A novel progestin receptor (mPR) with seven-transmembrane domains was recently discovered in spotted seatrout and homologous genes were identified in other vertebrates. We show that cDNAs for the mPR alpha subtypes from spotted seatrout (st-mPRalpha) and humans (hu-mPRalpha) encode progestin receptors that display many functional characteristics of G protein-coupled receptors. Flow cytometry and immunocytochemical staining of whole MDA-MB-231 cells stably transfected with the mPRalphas using antibodies directed against their N-terminal regions show the receptors are localized on the plasma membrane and suggest the N-terminal domain is extracellular. Both recombinant st-mPRalpha and hu-mPRalpha display high affinity (Kd 4.2-7.8 nm), limited capacity (Bmax 0.03-0.32 nm), and displaceable membrane binding specific for progestins. Progestins activate a pertussis toxin-sensitive inhibitory G protein (G(i)) to down-regulate membrane-bound adenylyl cyclase activity in both st-mPRalpha- and hu-mPRalpha-transfected cells. Coimmunoprecipitation experiments demonstrate the receptors are directly coupled to the G(i) protein. Similar to G protein-coupled receptors, dissociation of the receptor/G protein complex results in a decrease in ligand binding to the mPRalphas and mutation of the C-terminal, and third intracellular loop of st-mPRalpha causes loss of ligand-dependent G protein activation. Phylogenetic analysis indicates the mPRs are members of a progesterone and adipoQ receptor (PAQR) subfamily that is only present in chordates, whereas other PAQRs also occur in invertebrates and plants. Progesterone and adipoQ receptors are related to the hemolysin3 family and have origins in the Eubacteria. Thus, mPRs arose from Eubacteria independently from members of the GPCR superfamily, which arose from Archeabacteria, suggesting convergent evolution of seven-transmembrane hormone receptors coupled to G proteins.

The biogenic amine serotonin (5-HT) is a multi-faceted hormone that is synthesized from dietary t... more The biogenic amine serotonin (5-HT) is a multi-faceted hormone that is synthesized from dietary tryptophan with the rate limiting step being catalyzed by the enzyme tryptophan hydroxylase (TPH). The therapeutic potential of peripheral 5-HT synthesis inhibitors has been demonstrated in a number of clinical and pre-clinical studies in diseases including carcinoid syndrome, lung fibrosis, ulcerative colitis and obesity. Due to the long half-life of 5-HT in blood and lung, changes in steady-state levels are slow to manifest themselves. Here, the administration of stable isotope labeled tryptophan (heavy “h-Trp”) and resultant in vivo conversion to h-5-HT is used to monitor 5-HT synthesis in rats. Dose responses for the blockade of h-5-HT appearance in blood with the TPH inhibitors L-para-chlorophenylalanine (30 and 100mg/kg) and telotristat etiprate (6, 20 and 60mg/kg), demonstrated that the method enables robust quantification of pharmacodynamic effects on a short time-scale, opening the possibility for rapid screening of TPH1 inhibitors in vivo. In the bleomycin-induced lung fibrosis rat model, the mechanism of lung 5-HT increase was investigated using a combination of synthesis and steady state 5-HT measurement. Elevated 5-HT synthesis measured in the injured lungs was an early predictor of disease induced increases in total 5-HT.

Develop Biol, 2008

Optimal maturation of oocytes and successful development of preimplantation embryos is essential ... more Optimal maturation of oocytes and successful development of preimplantation embryos is essential for reproduction. We performed DNA microarray analyses of ovarian transcripts and identified glial cell line-derived neurotrophic factor (GDNF) secreted by cumulus, granulosa, and theca cells as an ovarian factor stimulated by the preovulatory LH/hCG surge. Treatment of cumulus-oocyte complexes with GDNF enhanced first polar body extrusion with increase in cyclin B1 synthesis and the GDNF actions are likely mediated by its receptor GDNF family receptor-alpha1 (GFRA1) and a co-receptor ret proto-oncogene (Ret), both expressed in oocytes. However, treatment with GDNF did not affect germinal vesicle breakdown and cytoplasmic maturation of oocytes. During the preimplantation stages, GDNF was expressed in pregnant oviducts and uteri, whereas GFRA1 and Ret were expressed in embryos throughout early development with an increase after the early blastocyst stage. In blastocysts, both GDNF and GFRA1 were exclusively localized in trophectoderm cells, whereas Ret was detected in both cell lineages. Treatment with GDNF promoted the development of two-cell-stage embryos into blastocysts showing increased cell proliferation and decreased apoptosis mainly in trophectoderm cells. Our findings suggest potential paracrine roles of GDNF in the promotion of completion of meiosis I and the development of early embryos.

Eur J Biochem, 1993

In the amphibian Xenopus Zuevis the D, dopamine receptor is involved in the regulation of the mel... more In the amphibian Xenopus Zuevis the D, dopamine receptor is involved in the regulation of the melanotrope cells of the intermediate pituitary during background adaptation of the animal. The Xenopus D, receptor has been found to be pharmacologically different from the mammalian D, receptor. In a number of mammalian species alternative splicing generates two molecular forms of the D, receptor. These isoforms differ by the presence or absence of 29 amino acids in the third cytoplasmic loop which is thought to be involved in guanine-nucleotide-binding-regulatory-protein (G-protein) binding of the receptor. We previously described a cDNA encoding the large isoform of the Xenopus D, receptor. Here we report on the isolation of a brain cDNA encoding a second, structurally different Xenopus D, dopamine receptor. Both Xenopus receptors correspond to the large isoform of the D, receptor and they display a high degree of sequence identity with their mammalian counterparts. Their occurrence reflects the expression of two Xenopus D, receptor genes and they are expressed to approximately the same level. In contrast to mammals, PCR analysis gave no evidence for alternative splicing during D, receptor expression in Xenopus brain and pituitary. Tissue-specific expression of the Xenopus D, receptor was observed in the pituitary during background adaptation. The low level of receptor mRNA in melanotrope cells of white animals compared to that of black animals may be caused by chronic dopamine stimulation of melanotrope cells in white animals with consequent cellular desensitization and down regulation of the D, receptor gene. Recent cloning of cDNA and genomic DNA fragments has revealed the existence of a number of dopamine-receptor subtypes, namely the D1, D,, DS, D, and D, receptors [l- 71. These receptors, which belong to the family of guaninenucleotide-binding-regulatory-protein(G-protein)-coupled receptors, are characterized by the presence of seven putative membrane-spanning domains within their structures [S]. The diversity of dopamine receptors is probably generated by gene duplication events. The D, and D, receptors are structurally and functionally related, and they are encoded by intronless genes. In contrast, the genes encoding the structurally and functionally related D,, D, and D, receptors all contain a number of introns. The structural and functional relationships between the dopamine-receptor subtypes D, and D, on the one hand, and DZ, D, and D4 on the other, may reflect their evolutionary history. In human, bovine, rat and

The TNFa-308*2 allele predicts non-response to remicade�

Dig Liver Dis, 2000

Bmc Bioinformatics, Feb 1, 2006

In the past years the Smith-Waterman sequence comparison algorithm has gained popularity due to i... more In the past years the Smith-Waterman sequence comparison algorithm has gained popularity due to improved implementations and rapidly increasing computing power. However, the quality and sensitivity of a database search is not only determined by the algorithm but also by the statistical significance testing for an alignment. The e-value is the most commonly used statistical validation method for sequence database searching. The CluSTr database and the Protein World database have been created using an alternative statistical significance test: a Z-score based on Monte-Carlo statistics. Several papers have described the superiority of the Z-score as compared to the e-value, using simulated data. We were interested if this could be validated when applied to existing, evolutionary related protein sequences.

Serum IL-5 and IL-13 consistently serve as the best predictors for the blood eosinophilia phenotype in adult asthmatics

Allergy, Jan 6, 2016

Molecular biomarkers that identify the phenotype of blood eosinophilia were evaluated in adult as... more Molecular biomarkers that identify the phenotype of blood eosinophilia were evaluated in adult asthmatics and their relationship with clinically significant asthma outcomes was assessed. Patients were clustered based on their molecular fingerprint. At inclusion, 64 patients were evaluated for phenotypic traits, sputum and blood eosinophilia, exhaled NO, serum cytokines and chemokines, total serum IgE, lung function (LF), airway hyperresponsiveness (AHR). Within-patient changes were evaluated in 44 patients six weeks later. Lung function, asthma control and monocyte chemotactic protein-1 (MCP-1) were identified as the most important distinguisher and blood eosinophilia as second most important identifier in principal component analysis. A robust relationship was observed between blood eosinophilia and IL-5, IL-13 and eosinophil-derived neurotoxin (EDN), which stayed consistent after 6 weeks. Serum IL-5 and IL-13 were the two best, followed by EDN as separators of high versus low bloo...

Pharmacokinetic/Pharmacodynamic Modelling of Receptor Internalization with CRTH2 Antagonists to Optimize Dose Selection

Clinical Pharmacokinetics, 2015

The role of ADME pharmacogenomics in early clinical trials: perspective of the Industry Pharmacogenomics Working Group (I-PWG)

Pharmacogenomics, Jan 30, 2015

Genetic polymorphisms in metabolizing enzymes and drug transporters have been shown to significan... more Genetic polymorphisms in metabolizing enzymes and drug transporters have been shown to significantly impact the exposure of drugs having a high dependence on a single mechanism for their absorption, distribution or clearance, such that genotyping can lead to actionable steps in disease treatment. Recently, global regulatory agencies have provided guidance for assessment of pharmacogenomics during early stages of drug development, both in the form of formal guidance and perspectives published in scientific journals. The Industry Pharmacogenomics Working Group (I-PWG), conducted a survey among member companies to assess the practices relating to absorption, distribution, metabolism, excretion pharmacogenomics) during early stages of clinical development, to assess the impact of the recent Regulatory Guidance issued by the US FDA and EMA on Industry practices.

This Provisional PDF corresponds to the article as it appeared upon acceptance. Copyedited and fully formatted PDF and full text (HTML) versions will be made available soon. Testing statistical significance scores of sequence comparison methods with structure similarity

BMC bioinformatics, Jan 12, 2006

Genome biology, 2006

The transfer of functional annotations from model organism proteins to human proteins is one of t... more The transfer of functional annotations from model organism proteins to human proteins is one of the main applications of comparative genomics. Various methods are used to analyze cross-species orthologous relationships according to an operational definition of orthology. Often the definition of orthology is incorrectly interpreted as a prediction of proteins that are functionally equivalent across species, while in fact it only defines the existence of a common ancestor for a gene in different species. However, it has been demonstrated that orthologs often reveal significant functional similarity. Therefore, the quality of the orthology prediction is an important factor in the transfer of functional annotations (and other related information). To identify protein pairs with the highest possible functional similarity, it is important to qualify ortholog identification methods. To measure the similarity in function of proteins from different species we used functional genomics data, s...