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Biomedical subjects

Cees B M Oudejans

Publications and source records attributed to Cees B M Oudejans.

At least 19 recordsLinked to original sources
PubMed2006

Genetics of preeclampsia: paradigm shifts.

Segregation of preeclampsia into early-onset, placental and late-onset, maternal subtypes along with the acknowledgement of the contribution of epigenetics in placentally expressed genes proved to be a key first step in the identification of essential gene variants associated with preeclampsia. Application of this insight to other populations and related pregnancy-induced syndromes, such as HELLP, and acknowledgment of the features shared between chromosomal loci associated with preeclampsia in different populations provide the rationale for new strategies for the identification of susceptibility genes and for new and more effective diagnostic strategies.

Chromosome Mapping↗
PubMed2005

Expression microarray analysis and oligo array comparative genomic hybridization of acquired gemcitabine resistance in mouse colon reveals selection for chromosomal aberrations.

Gemcitabine is a commonly used therapy for many solid tumors. Acquired resistance to this nucleoside analogue, however, diminishes the long-term effectiveness in a majority of patients. To better define the molecular background of gemcitabine resistance, a mouse colon tumor was selected during successive rounds of transplantation with continued treatment of gemcitabine. Expression microarray analysis was applied to determine which genes are consistently and highly overexpressed or underexpressed in the resistant versus the nonresistant tumor. For the statistical interpretation of the microarray data, a parametric model was implemented, which returns model-based differential gene expression (log-) ratios and their uncertainties. This defined a set of 13 genes, putatively responsible for the gemcitabine resistance in solid tumors. One of these, RRM1, was previously identified as an important marker for gemcitabine resistance in human cell lines. Five of the 13 genes, including RRM1, are located within a 3 Mb region at chromosome 7E1 of which four are highly overexpressed, suggesting a chromosomal amplification. Therefore, chromosomal copy number changes were measured, using oligo array comparative genomic hybridization. A narrow and high amplification area was identified on 7E1 that encompassed all five genes. In addition, reduced RNA expression of two other genes at 8E1 encoding COX4I1 and RPL13 could be explained by a decrease in chromosomal copy number on chromosome 8. In conclusion, the array comparative genomic hybridization biologically validates our statistical approach and shows that gemcitabine is capable to select for chromosomally aberrant tumor cells, where changed gene expression levels lead to drug resistance.

Animals↗
PubMed2005

Detection of the placental epigenetic signature of the maspin gene in maternal plasma.

The discovery of fetal DNA in the plasma of pregnant women has opened up new approaches for noninvasive prenatal diagnosis and monitoring. Up to now, the lack of a fetal DNA marker that can be universally detected in maternal plasma has limited the clinical application of this technology. We hypothesized that epigenetic differences between the placenta and maternal blood cells could be used for developing such a marker. By using bisulfite DNA sequencing, the methylation status of the maspin gene promoter in placental tissues and paired maternal blood cells from pregnant women was analyzed. The maspin gene promoter was found to be hypomethylated in placental tissues and densely methylated in maternal blood cells. Genotyping of a single nucleotide polymorphism within the unmethylated maspin sequences in maternal plasma demonstrated that these sequences were derived from the fetus. By using real-time quantitative methylation-specific PCR, unmethylated maspin sequences were detected in maternal plasma in all three trimesters of pregnancy and were cleared within 24 h after delivery. The maternal plasma concentration of unmethylated maspin sequences was elevated by a median of 5.7 times in preeclamptic pregnancies compared with nonpreeclamptic pregnancies. Hypomethylated maspin DNA is the first universal marker for fetal DNA in maternal plasma, thus allowing the measurement of fetal DNA concentrations in pregnancy-associated disorders, irrespective of fetal gender and genetic polymorphisms. Differential DNA methylation between the placenta and maternal blood cells may be exploited to develop further markers for noninvasive prenatal assessment.

Adult↗
PubMed2005

Novel biomarkers in preeclampsia.

Preeclampsia is a pregnancy-associated disease with maternal symptoms, but placental origin. Although clinical symptoms are late, systemic and maternal, the origin of preeclampsia is early, local and placental. Despite that various protein biomarkers display changed levels in maternal serum at presymptomatic stages, they lack discriminative and predictive power in individual patients. In contrast to protein markers, placental RNA analyzed in maternal plasma permits rapid screening of novel biomarkers including markers not accessible by antibody based assays. This includes transcription factors, non-coding RNA, epigenetic features, as well as genes functionally or genetically linked with preeclampsia. By reviewing genes with placental expression in the Human SymAtlas and comparison with proven qualifiers, a large set of RNA biomarkers was targeted for use in maternal plasma. These biomarkers qualify as novel RNA biomarkers for the presymptomatic detection in first trimester of pregnancy-associated diseases with placental origin and/or dysfunction such as pregnancy-induced hypertension without or with proteinuria (preeclampsia), the HELLP syndrome, and intrauterine growth restriction.

Biomarkers↗
PubMed2005

Maternal segregation of the Dutch preeclampsia locus at 10q22 with a new member of the winged helix gene family.

Preeclampsia is a pregnancy-associated disease with maternal symptoms but placental origin. Epigenetic inheritance is involved in some populations. By sequence analysis of 17 genes in the 10q22 region with maternal effects, we narrowed the minimal critical region linked with preeclampsia in the Netherlands to 444 kb. All but one gene in this region, which lies within a female-specific recombination hotspot, encode DNA- or RNA-binding proteins. One gene, STOX1 (also called C10orf24), contained five different missense mutations, identical between affected sisters, cosegregating with the preeclamptic phenotype and following matrilineal inheritance. Four STOX1 transcripts are expressed in early placenta, including invasive extravillus trophoblast, generating three different isoforms. All contain a winged helix domain related to the forkhead (FOX) family. The largest STOX1 isoform has exclusive nuclear or cytoplasmic expression, indicating activation and inactivation, respectively, of the PI3K-Akt-FOX pathway. Because all 38 FOX proteins and all 8 STOX1 homologs have either tyrosine or phenylalanine at position 153, the predominant Y153H variation is highly mutagenic by conservation criteria but subject to incomplete penetrance. STOX1 is a candidate for preeclampsia controlling polyploidization of extravillus trophoblast.

Chromosomes, Human, Pair 10↗
PubMed2005

MLC1: a novel protein in distal astroglial processes.

Megaloencephalic leukoencephalopathy with subcortical cysts (MLC) is a progressive cerebral white matter disease in children caused by mutations in the MLC1 gene. This disease is histopathologically characterized by myelin splitting and intramyelinic vacuole formation. MLC1 encodes a novel protein, MLC1, which is mainly expressed in the brain and leukocytes. The function is unknown, although a transport function has been suggested. In this article, we provide experimental data addressing the membrane topology and cellular localization of MLC1. We show that MLC1 contains an even number of transmembrane domains, supporting the possible transport function of MLC1. We demonstrate that MLC1 is specifically expressed in distal astroglial processes in perivascular, subependymal, and subpial regions. This localization suggests a role for MLC1 in a transport process across the blood-brain and brain-cerebrospinal fluid barriers. Astrocyte functions have long been debated. It is becoming increasingly clear that these cells are of fundamental importance in maintaining the structural and functional integrity of neural tissue. Elucidation of the function of MLC1 will contribute to a better understanding of not only the pathophysiology of the disease, but also the role of astrocytes in normal neural tissue.

Amino Acid Sequence↗
PubMed2004

The parent-of-origin effect of 10q22 in pre-eclamptic females coincides with two regions clustered for genes with down-regulated expression in androgenetic placentas.

By affected sib-pair linkage analysis of 24 families with pre-eclampsia, we confirm a susceptibility locus on chromosome 10q22.1 in Dutch females: a multipoint non-parametric linkage score of 3.6 near marker D10S1432 was obtained. Haplotype analysis showed a parent-of-origin effect: maximal allele sharing in the affected sibs was found for maternally derived alleles in all families, but not for the paternally derived alleles. As matrilineal inheritance suggests the presence of maternally expressed imprinted genes, while imprinting operates predominantly in (extra)embryonic tissues, all genes (n=132) known on 10q22 between GATA121A08 and D10S580 were screened for seven sequence-related features associated with imprinting and subsequently tested for expression in first trimester placenta. Placental expression of genes selected in this way (n=55) was compared with expression in androgenetic placentas of identical gestational age. Two regions on 10q22 were identified with developmentally co-repressed genes with non-random chromosomal distribution. Interestingly, these two clusters, near CTNNA3 and KCNMA1 and each containing five genes with down-regulated expression in androgenetic placentas, coincided with the regions with maximal maternal allele sharing seen in the pre-eclamptic sisters. Our linkage and expression data are compatible with the concept that pre-eclampsia involves maternally expressed imprinted genes that operate in the first trimester placenta.

Alleles↗
PubMed2004

NEUROD1 acts in vitro as an upstream regulator of NEUROD2 in trophoblast cells.

The basic helix-loop-helix (bHLH) transcription factors NEUROD1, NEUROD2 and ATH2 are expressed during first trimester human placental development. We determined the transactivation potential of each of these factors in trophoblasts by measuring changes in the endogenous gene activity using absolute quantification by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) after transient transfection. In these assays, NEUROD1 was found to transiently transactivate NEUROD2 in trophoblast cells. Promotor truncation assays, using luciferase constructs, showed the presence of two domains in the NEUROD2 promotor, which showed increased activity after NeuroD1 transfection. Each of these NeuroD1-responsive domains contains an E-box sequence. The NEUROD2 transactivation data fit with the spatial expression pattern of NEUROD1 and NEUROD2, since they are expressed in endovascular trophoblasts. This expression pattern, as well as the present transactivation results, might suggest the presence of a NEUROD differentiation cascade during first trimester human placental development.

Basic Helix-Loop-Helix Proteins↗
PubMed2004

C2360, a nuclear protein expressed in human proliferative cytotrophoblasts, is a representative member of a novel protein family with a conserved coiled coil-helix-coiled coil-helix domain.

In this study, we describe the identification of nine novel genes isolated from a unique human first-trimester cDNA library generated from the placental bed. One of these clones, called C2360 and located on chromosome 10q22, was selected as it showed restricted expression in placental bed tissue as well as in JEG3 choriocarcinoma cells with absent expression in adult tissues. We show that the expression is restricted to first-trimester proliferative trophoblasts of the proximal column and show that C2360 is a nuclear protein. No detectable transactivation potential was observed for different domains of the protein. Secondary structure prediction showed that C2360 is a representative member of a eukaryotic family of proteins with a low conservation at the amino acid level, but with strong conservation at the structural level, sharing the general domain (coiled coil 1)-(helix 1)-(coiled coil 2)-(helix 2), or CHCH domain. Each alpha-helix within this domain contains two cysteine amino acids, and these intrahelical cysteines are separated by nine amino acids (C-X(9)-C motif). The fixed position within each helix indicated that both helices could form a hairpin structure stabilized by two interhelical disulfide bonds. Other proteins belonging to the family include estrogen-induced gene 2 and the ethanol-induced 6 protein. The conserved motif was found in yeast, plant, Drosophila, Caenorhabditis elegans, mouse, and human proteins, indicating that the ancestor of this protein family is of eukaryotic origin. These results indicate that C2360 is a representative member of a multifamily of proteins, sharing a protein domain that is conserved in eukaryotes.

Amino Acid Sequence↗
PubMed2004

Markers for presymptomatic prediction of preeclampsia and intrauterine growth restriction.

Preeclampsia and intrauterine growth restriction are both characterized by placental malfunction. The pathological processes of abnormal trophoblast invasion, partial absence of maternal spiral artery modification, increased apoptosis of trophoblast cells, and placental ischemia are all associated with the release of specific molecules. These proteins, as well as cell-free fetal DNA and RNA might be detected in the maternal peripheral circulation, quantified, and used for early identification and prediction of preeclampsia and intrauterine growth restriction, prior to the appearance of the clinical symptoms. As preeclampsia and intrauterine growth restriction are associated with increased maternal, perinatal, and neonatal morbidity and mortality, early identification of these pregnancy associated complications will permit the design of appropriate preventive measures. In this review a variety of factors reported to be useful as potential markers for early detection of pregnancies at increased risk will be discussed. Molecules associated with the establishment of the placenta and essential in fetal-maternal interactions, like interleukin 2-receptor, insulinlike growth factor-1, and insulinlike growth factor binding protein-1, placenta growth factor, hepatocyte growth factor, inhibin A, activin A, and human chorionic gonadotrophin seem to be the most likely candidates for presymptomatic markers for preeclampsia and/or intrauterine growth restriction. Detection and discrimination of these molecules through the placental RNA in maternal plasma based strategy has become a realistic option.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2004

Neurokinin B levels in maternal circulation during early pregnancy.

Neurokinin B levels were measured between the 10th-20th weeks of pregnancy, i.e., prior to the development of clinical symptoms, in women who developed preeclampsia or delivered a growth-restricted baby. No difference was found in plasma neurokinin B levels, although neurokinin B levels increased slightly towards term.

Adult↗
PubMed2003

The cellular Pax-Hox-helix connection.

Basic helix-loop-helix (bHLH) transcription factors are important regulators of lineage determination during embryogenesis. Initial experiments in Drosophila showed that early neural selection and specification are dependent on atonal (ato) and members of the achaete-scute complex (as-c). In mammals, transcription factors homologous to as-c and ato are causally involved during development of organs throughout the body. Development of subsets of lineages in intestine, stomach, pancreas, lung, thyroid and placenta have been shown to be regulated by members of the as-c and ato families. These functional studies show that an individual bHLH transcription factor can regulate multiple developmental processes throughout the mammalian body, which implicates that extant as-c and ato transcription factors play a distinct function dependent on their cellular context. Based on the synergistic activation of the insulin, POMC and Pax4 promotors by bHLH and homeobox (Hox) protein complexes, we hypothesize that the underlying cellular function-modulating factors include members of the Hox and paired box (Pax) multigene families. These examples indicate that unique combinations of bHLH and Hox proteins, mediated by protein-protein interactions, might be responsible for activating cell-specific sets of target genes.

Animals↗
PubMed2003

Plasma hepatocyte growth factor as a marker for small-for-gestational age fetuses.

OBJECTIVE: To study the association between hepatocyte growth factor (HGF) levels and pregnancy outcome. STUDY DESIGN: Hepatocyte growth factor levels were measured in 42 plasma samples between weeks 14 and 21 of gestation using an enzyme-linked immunosorbent assay (ELISA). Results were correlated to pregnancy outcome and Mann-Whitney U-test applied to study the differences. RESULTS: Hepatocyte growth factor values in pregnancies that develop preeclampsia (n=12) were not significantly different from unaffected pregnancies (n=21, multiples of the median (MoM)=1.38, P=0.47). However, hepatocyte growth factor values were significantly elevated in pregnancies of small-for-gestational age (SGA) fetuses (n=9) compared to uncomplicated pregnancies (MoM=2.66, P<0.001). CONCLUSION: Measurement of hepatocyte growth factor in peripheral blood between 14 and 21 weeks gestation may offer new possibilities in the early diagnosis and prediction of fetal birth weight but not of preeclampsia.

Biomarkers↗
PubMed2003

Circulating trophoblast in maternal blood.

This review describes the status of circulating trophoblast, but is considered in the perspective that only a specific subset of trophoblast cells circulates in the maternal blood. The consequences for isolation, identification and clinical potential are described.

Adult↗
PubMed2003

Detection of chromosome 21-encoded mRNA of placental origin in maternal plasma.

BACKGROUND: mRNA of placental origin (i.e., human placental lactogen and beta-human chorionic gonadotropin) has been demonstrated to be easily detectable in maternal plasma. We tested whether detection of chromosome 21-encoded mRNA of placental origin is possible in maternal plasma obtained during the first trimester. METHODS: Plasma samples were obtained from pregnant women between weeks 9-13 of pregnancy. RNA was isolated from 800 or 1600 microL of plasma by silica-based affinity isolation and, after on-column DNase treatment, was subjected to two-step, one-tube reverse transcription-PCR with gene specific primers. RESULTS: Three chromosome 21-encoded genes located within the Down syndrome critical region with overexpression in trisomy 21 placentas were screened for expression in early placental tissue to select their potential use for RNA based plasma screening. One of the chromosome 21-encoded genes (LOC90625) showed strong expression in first trimester placenta similar to CSH1 (human placental lactogen) and was selected for plasma analysis. The RNA isolation assay was validated with CSH1 mRNA, which could be detected in the plasma of all women tested in weeks 9-13 of pregnancy. RNA from the chromosome 21-encoded, placentally expressed gene, LOC90625, was present in maternal first-trimester plasma and could be detected in 60% of maternal plasma samples when 800 microL of plasma was used and in 100% of samples when 1600 microL of plasma was used. CONCLUSION: The detection of chromosome 21-encoded mRNA of placental origin in maternal plasma during the first trimester may allow development of plasma-RNA-based strategies for prenatal prediction of Down syndrome. LOC90625 is a candidate gene for this purpose.

Chromosomes, Human, Pair 21↗
PubMed2002

Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.

Leukoencephalopathy with vanishing white matter is a recently defined autosomal recessive disorder. The course is chronic progressive with additional episodes of rapid deterioration, provoked by fever and minor head trauma. A previous study showed that mutations in the genes encoding the epsilon- or the beta-subunit of the eukaryotic translation initiation factor eIF2B, a complex consisting of five subunits, cause the disease in most patients. Seven unsolved patients remained. The unsolved patients were investigated by mutation analysis of the genes encoding the alpha-, gamma-, and delta-subunit of eIF2B and the gene encoding the alpha-subunit of eIF2, because phosphorylation of this latter subunit regulates eIF2B activity. Mutations were found in the genes encoding the alpha- (1 patient), gamma- (2 patients), and delta-subunits (2 patients) of eIF2B, but no mutations were found in the gene encoding the alpha-subunit of eIF2. In 2, both less typical patients, no mutations were found. Mutations in all five genes eIF2B subunit genes can cause VWM. eIF2B is essential for the initiation of translation of RNA into protein and is involved in regulation of the process, especially under circumstances of stress, such as fever. A defect in eIF2B may explain the sensitivity to stress factors in vanishing white matter patients.

Brain Diseases↗
PubMed2002

The proneural genes NEUROD1 and NEUROD2 are expressed during human trophoblast invasion.

During early human pregnancy, extravillous trophoblast cells invade the maternal tissue of the uterus in a way similar to invasion by cancer cells. However, the process of trophoblast invasion is regulated in a time and place restricted way, in contrast to cancer invasion. We screened first trimester placental tissue enriched by extravillous invasive trophoblasts for the expression of proneural basic helix-loop-helix (bHLH) transcription factors, which are important controllers of cell fate. Surprisingly, the presence of NEUROD1, NEUROD2 and ATH2 transcripts was found by reverse transcriptase polymerase chain reaction (RT-PCR) analysis in first trimester placentabed. Of these genes, the proneural genes NEUROD1 and NEUROD2 are expressed in different subsets of invasive trophoblasts. NEUROD1 expression is found in interstitial and endovascular invasive cells, while NEUROD2 expression is observed mainly in endovascular invasive cells, respectively. These data suggest that in addition to the involvement of proneural genes in neuron, neurendocrine and pancreas differentiation, these genes are involved in trophoblast differentation during progression of invasion.

Annexins↗