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Results for “Receptor, Notch4”

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PubMed2003

NOTCH4 and the frontal lobe in schizophrenia.

NOTCH4 is a developmentally expressed gene recently reported to be in linkage disequilibrium (LD) with schizophrenia. We investigated this finding in our sample of subjects, focusing on an exonic (CTG)(n) polymorphism, examining not only the association of this polymorphism with the disease phenotype, but also its effect on frontal lobe brain morphology and cognitive function in both affected individuals and a psychiatrically normal comparison group. While we did not find any association or LD with schizophrenia, we identified striking effects of NOTCH4 variability on the trait measures. Within the respective schizophrenia and comparison groups, NOTCH4 allelic variability was correlated with differences in measures of frontal lobe cognitive performance and frontal lobe brain tissue volumes that were intuitively congruent. These within-group effects, however, were in opposite directions across groups. These findings may reflect the interaction of NOTCH4 with the underlying genetic and phenotypic complexity that characterizes both schizophrenia and normal cognition and brain development.

Adult↗

PubMed2007

Association study between the TNXB locus and schizophrenia in a Japanese population.

The chromosome 6p21-24 region, which contains the human leukocyte antigen (HLA) region, has been suggested as an important locus for a susceptibility gene for schizophrenia. Recently, a significant association between schizophrenia and the TNXB locus, located immediately telomeric of the NOTCH4 locus in the HLA region, was observed. Few studies have further investigated the region in schizophrenia. In the present study, we investigated the region in a Japanese population. Subjects included 241 patients with schizophrenia and 290 controls. Twenty-six single nucleotide polymorphisms (SNPs) and the corresponding haplotypes were analyzed. As a result, exactly the same SNPs in the TNXB locus (rs1009382 and rs204887) as in the previous study were associated with schizophrenia (P = 0.034 and 0.034, respectively, uncorrected). A SNP (rs2071287) in the NOTCH4 locus and haplotype around it were also suggested to associate with the disease, consistent with another previous study (P = 0.041 and permutation P = 0.024, respectively, uncorrected). Although these associations became insignificant after Bonferroni correction, the findings might provide support for the association of the TNXB locus or its adjacent region of the NOTCH4 locus with schizophrenia.

Adult↗

PubMed2002

Genetic analysis of the (CTG)n NOTCH4 polymorphism in 65 multiplex bipolar pedigrees.

A strong genetic association between the NOTCH4 locus on chromosome 6 and schizophrenia was recently reported. Based on the data suggesting overlapping susceptibility for schizophrenia and bipolar disorder, we genotyped the polymorphic (CTG)n encoding polyleucine repeat in exon 1 of NOTCH4 in 65 pedigrees ascertained for a genetic linkage study of bipolar disorder. In addition, we analyzed a subset of our pedigrees with psychotic features at this locus. We failed to find any association between the (CTG)n NOTCH4 polymorphism and either the bipolar or the psychotic bipolar phenotype in our 65 pedigrees.

Base Sequence↗

PubMed2004

Neither single-marker nor haplotype analyses support an association between genetic variation near NOTCH4 and bipolar disorder.

Markers near the NOTCH4 locus on chromosome 6p21.3 have been reported to be associated with schizophrenia in some studies. Since schizophrenia and bipolar affective disorder (BPAD) may share genetic determinants, we tested markers in and near NOTCH4 in a sample of 153 parent-offspring triads ascertained through a sibling pair with BPAD for evidence of association. This sample would have 80% power to detect an association at or above a genotype relative risk of 2.4 at the 10(-7) level of significance. In addition to the two markers previously showing the most significant association with schizophrenia, three additional nearby markers were studied. The five markers were genotyped using validated methods. Both single-marker and 3-marker haplotype data was analyzed using family-based association methods. No genome-wide significant association was detected between any of the five SNP-markers and BPAD in this sample. One marker showed nominal evidence of association (P = 0.049), but this evidence was not supported by haplotype analyses including nearby flanking markers or by case-control analysis using 93 Caucasian controls. These results do not support an association between genetic variation near NOTCH4 and BPAD in this sample.

Alleles↗

PubMed2004

Transmission disequilibrium test and haplotype analysis of the NOTCH4 gene in Japanese patients with schizophrenia.

A recent study reported that the NOTCH4 gene was highly associated with schizophrenia in the British population. To confirm this association for another population, a case-control study was conducted and a transmission disequilibrium test (TDT) analysis was performed on a group of Japanese subjects (235 pairs of schizophrenia patients and controls, and 78 trios consisting of probands and their parents) using two single nucleotide polymorphisms and three microsatellite markers for the NOTCH4 gene. Haplotype analysis was also studied in case-control and family based data sets. In all markers except for (CTG)n (P = 0.012, before correction for multiple testing), no differences were found in the case-control study. The TDT analysis also revealed only a weak transmission disequilibrium in (TTAT)n (genotype-wise P = 0.012). The finding of the present study could not support the original findings that the NOTCH4 gene itself is associated with susceptibility to schizophrenia.

Adult↗

PubMed2000

Imbalanced expression of TAN-1 and human Notch4 in endometrial cancers.

The development of cancer is a cellular process that reflects and is partly driven by alterations in cell determination. Mutations in various genes responsible for cell determination have been identified as being oncogenic; however, little is known about the involvement of normal cell fate-determining mechanisms in the oncogenic process. The Notch pathway is an evolutionarily conserved, general cell-interaction mechanism that controls fundamental aspects of cell determination during the development of vertebrates and invertebrates. We have explored the roles of the recently cloned human Notch4 gene, which is a homologue of Drosophila Notch, in endometrial tissue, a cellular environment where cell fate changes take place and neoplastic conditions have been characterized. Northern blot analysis, dot blot analysis, and in situ hybridization were performed on samples of normal endometria at different phases of the menstrual cycle and endometrial cancers. Our results showed that: a) Both human Notch4 and translocation-associated Notch homologue-1 (TAN-1), another human homologue of Drosophila Notch, are expressed in the normal endometrium, mainly in the endometrial glandular cells. b) The level of expression of human Notch4, but not TAN-1, changes during the normal menstrual cycle; i.e., the level of Notch4 expression was significantly lower during the secretory phase than during the proliferative phase. c) Endometrial cancers express a significantly lower level of human Notch4 and a significantly higher level of TAN-1 than normal endometria. These results suggest that human Notch4 and/or TAN-1 are involved in the changes of the endometrium during the menstrual cycle, and also in the development of endometrial cancer.

Adenocarcinoma↗

PubMed2005

Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function.

Delta-like 4 (Dll4), a membrane-bound ligand for Notch1 and Notch4, is selectively expressed in the developing endothelium and in some tumor endothelium, and it is induced by vascular endothelial growth factor (VEGF)-A and hypoxia. Gene targeting studies have shown that Dll4 is required for normal embryonic vascular remodeling, but the mechanisms underlying Dll4 regulatory functions are currently not defined. In this study, we generated primary human endothelial cells that overexpress Dll4 protein to study Dll4 function and mechanism of action. Human umbilical vein endothelial cells retrovirally transduced with Dll4 displayed reduced proliferative and migratory responses selectively to VEGF-A. Expression of VEGF receptor-2, the principal signaling receptor for VEGF-A in endothelial cells, and coreceptor neuropilin-1 was significantly decreased in Dll4-transduced endothelial cells. Consistent with Dll4 signaling through Notch, expression of HEY2, one of the transcription factors that mediates Notch function, was significantly induced in Dll4-overexpressing endothelial cells. The gamma-secretase inhibitor L-685458 significantly reconstituted endothelial cell proliferation inhibited by immobilized extracellular Dll4 and reconstituted VEGFR2 expression in Dll4-overexpressing endothelial cells. These results identify the Notch ligand Dll4 as a selective inhibitor of VEGF-A biologic activities down-regulating 2 VEGF receptors expressed on endothelial cells and raise the possibility that Dll4 may be exploited therapeutically to modulate angiogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Is NOTCH4 associated with schizophrenia?

The NOTCH4 locus was reported to be associated with schizophrenia in our previous study but the subsequent replication by other workers has been inconsistent. To find out possible reasons for the poor replication, the present work was undertaken to analyse four functional single nucleotide polymorphisms (SNPs) (rs367398, rs915894, rs520692 and rs422951) at the NOTCH4 locus among 141 schizophrenic family trios of Chinese Han descent. Of these four SNPs, rs520692 was the only one associated with schizophrenia (P = 0.017); the other three, however, did not show any association with the illness, including rs367398 located in the promoter region, which had shown a strong association with the illness in our previous study conducted with British samples. Although these four SNPs analysed lie within a less than 4 kb segment of genomic DNA, the pattern of linkage disequilibrium between them was unexpected. The strongest linkage disequilibrium was shown only between rs367398 and rs520692 and between rs520692 and rs422951 in both parent and patient groups. This study raises the possibility that there might be two or more disease-underlying variants at the NOTCH4 locus or at a nearby locus, and that the allelic or locus heterogeneity may be one of the possible reasons for the poor replication of the NOTCH4 finding.

Adult↗

PubMed2003

Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development.

Mammalian Fbw7 (also known as Sel-10, hCdc4, or hAgo) is the F-box protein component of an SCF (Skp1-Cul1-F-box protein-Rbx1)-type ubiquitin ligase, and the mouse Fbw7 is expressed prominently in the endothelial cell lineage of embryos. We generated mice deficient in Fbw7 and found that the embryos died in utero at embryonic day 10.5-11.5, manifesting marked abnormalities in vascular development. Vascular remodeling was impaired in the brain and yolk sac, and the major trunk veins were not formed. In vitro para-aortic splanchnopleural explant cultures from Fbw7(-/-) embryos also manifested an impairment of vascular network formation. Notch4, which is the product of the proto-oncogene Int3 and an endothelial cell-specific mammalian isoform of Notch, accumulated in Fbw7(-/-) embryos, resulting in an increased expression of Hey1, which encodes a transcriptional repressor that acts downstream of Notch signaling and is implicated in vascular development. Expression of Notch1, -2, or -3 or of cyclin E was unaffected in Fbw7(-/-) embryos. Mammalian Fbw7 thus appears to play an indispensable role in negative regulation of the Notch4-Hey1 pathway and is required for vascular development.

Animals↗

PubMed2005

[Association study of NOTCH4 gene polymorphisms with schizophrenia and mood disorders in mixed pedigrees].

This study was to explore the relationships between NOTCH4 gene and schizophrenia (SP) and mood disorders (MD), and to search for a common susceptible gene for SP and MD in Chinese Han population. We collected 61 mixed pedigrees of SP and MD in Chinese Han population. NOTCH4 polymorphisms -1725T/G and-25T/C were genotyped by applying PCR-RLFP technique, then transmission disequilibrium test (TDT) and haplotype-based haplotype relative risk analysis(HHRR) were performed. The results showed that -1725T/G was not associated with SP or MD (P>0.05), -25T/C was not associated with SP (P>0.05), but associated significantly with MD for female or early-onset (age of onset 0.05). Our results suggested NOTCH4 or neighboring gene might be a common susceptible gene for SP and MD in the pedigrees studied.

Adult↗

PubMed2001

NOTCH4 gene polymorphism and susceptibility to schizophrenia and schizoaffective disorder.

The NOTCH4 gene is located at 6p21.3, a site which several studies have shown to have significant linkage with schizophrenia. Recently, an exceptionally strong association was reported between NOTCH4 gene polymorphisms and schizophrenia in British patients. We re-examined their findings using a Japanese population. We genotyped three kinds of polymorphisms, SNP1 in the 5' flanking region, SNP2 in the promoter region and CTG repeats in exon 1 of the NOTCH4 gene of schizophrenics (N=188), patients with schizoaffective disorder (N=39) and controls (N=143). Genotypic distributions and allelic frequencies of SNP1, SNP2 and CTG repeats of the NOTCH4 gene did not show significant associations with schizophrenia or schizoaffective disorder. Neither they showed association with schizophrenia subcategories, hebephrenic and paranoid type schizophrenia, nor with subgroups of schizophrenia with and without positive family history of psychoses. The present study found that the NOTCH4 gene does not confer susceptibility to schizophrenia and schizoaffective disorders, at least in Japanese subjects, in contrast to the findings in British subjects.

Adult↗

PubMed2005

An 8-bp deletion in mNOTCH4 intron 10 leads to its retention in mRNA and to synthesis of a truncated protein.

Notch signaling participates in the development of multicellular organisms by maintaining self-renewal potential or inducing differentiation of numerous tissues. In this study, we characterized Notch4, the evolutionary most distant and least studied Notch family member. We identified a Notch4 inter-strain polymorphism with a previously undescribed mRNA variant. This longer Notch4 mRNA, which represented up to one-third of total Notch4 mRNA, resulted from intron 10 retention. Analysis of Notch4 intron 10 revealed that an 8-bp deletion, reducing its length from 68 to 60 bp, strictly correlated with its retention. Further experiments demonstrated that intron length was the only cause of the mis-splicing. Moreover, this mRNA variant resulted in a truncated protein containing half the extracellular domain of Notch4, including the ligand-binding domain.

Amino Acid Sequence↗

PubMed1996

Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene.

The int-3 oncogene was identified as a frequent target in Mouse Mammary Tumor Virus (MMTV)-induced mammary carcinomas and encodes the intracellular domain of a novel mouse Notch gene. To investigate the role of the int-3 proto-oncogene in mouse development and carcinogenesis, we isolated cDNA clones corresponding to the entire coding potential of the int-3 proto-oncogene. We propose to name this gene Notch4 and reserve the int-3 nomenclature for references to the oncogenic form. The deduced amino acid sequence of Notch4 contains conserved motifs found in Notch proteins; however Notch4 has fewer epidermal growth factor (EGF)-like repeats and a shorter intracellular domain than other mouse Notch homologues. Comparison of the coding potential of the int-3 gene to that of Notch4 suggests that loss of the extracellular domain of Notch4 leads to constitutive activation of this murine Notch protein. In situ hybridization revealed that Notch4 transcripts are primarily restricted to endothelial cells in embryonic and adult life. Truncated Notch4 transcripts were detected in post-meiotic male germ cells. The distinct Notch4 protein features and its restricted expression pattern suggests a specific role for Notch4 during development of vertebrate endothelium.

Amino Acid Sequence↗

PubMed1997

Triplet repeat polymorphism within the NOTCH4 gene located near the junction of the HLA class II and class III regions in narcolepsy.

A polymorphic (CTG)n microsatellite repeat was found in the signal peptide domain of the NOTCH4 gene located near the junction of the class II and class III regions of the human major histocompatibility complex. This gene belongs to a multigene family of NOTCH originally identified as a differential factor of neuronal cells. To ascertain whether the NOTCH4 gene is involved in the development of neurogenic disease, narcolepsy, which is known to be tightly associated with HLA-DR15, this microsatellite polymorphism of the (CTG)n repeat was analyzed in Japanese patients with narcolepsy One allele, 9 repetitions of CTG (Leu) was significantly increased in the patient group. However, the significant increase of this allele in the patient group could be explained by a strong linkage disequilibrium with the HLA class II alleles, DRB1*1501, DQA1*0102 and DQB1*0602, which were more strongly associated with the disease. These results suggest that the (CTG)n repeat polymorphism in NOTCH4 does not primarily determine the susceptibility to narcolepsy.

Alleles↗

PubMed2006

Genetic association between Notch4 polymorphisms and Japanese schizophrenics.

The objective of this study was to investigate whether three single nucleotide polymorphisms of the Notch4 gene are associated with the onset of schizophrenia. To confirm the linkage disequilibrium among these three single nucleotide polymorphisms of the gene, the three single nucleotide polymorphisms were genotyped by a polymerase chain reaction-restriction-fragment length polymorphism method for all samples. The genotypic frequencies of each single nucleotide polymorphism in the schizophrenic were compared with respective controls using a chi method. To check linkage disequilibrium, the haplotype frequency program was utilized. No statistical association between the two single nucleotide polymorphisms of the Notch4 gene and schizophrenia was observed in our Japanese samples. Although one nonsynonymous single nucleotide polymorphism did show a weakly significant P-value, its allelic frequencies are not positive. Two of the single nucleotide polymorphisms showed strong linkage disequilibrium in our Japanese samples. The single nucleotide polymorphism between the other two single nucleotide polymorphisms showed a weaker linkage disequilibrium with the others. Our study suggests that the three single nucleotide polymorphisms are not associated with the onset of schizophrenia. The linkage disequilibrium of this locus indicates that there is genetic heterogeneity in the Notch4 gene. Linkage disequilibrium may differ among ethnic groups, and so a larger study should be performed in this region.

5' Untranslated Regions↗

PubMed2004

Association of six polymorphisms of the NOTCH4 gene with schizophrenia in the Japanese population.

The NOTCH4 gene is located at 6p21.3 and involved in the development and patterning of the central nervous systems. Recently, Wei and Hemmings [2000] observed that the gene was associated with schizophrenia. Subsequent to the report, several studies investigated the gene in schizophrenia, with controversial and inconclusive results. In the present study, we investigated six polymorphisms (SNPs 1-5 and a CTG repeat) of the gene in Japanese subjects with schizophrenia (n = 284) and the same number of controls. The polymorphisms include SNP5, which has been observed to be associated with schizophrenia in a Chinese population and two new SNPs 3-4 adjacent to SNP5, in addition to the SNPs 1-2 and the CTG repeat, which were suggested for the association with the disease in the previous study. As a result, no significant difference in genotypic distributions or allelic frequencies of the six polymorphisms of the gene was observed between the patients and the controls. Also, no significant difference was found in frequencies of haplotypes of the six polymorphisms between the patients and the controls. However, the distribution of SNP2 was significantly deviated from Hardy-Weinberg equilibrium in the patients (P = 0.000986), not in the controls, which could be a chance or due to an association of SNP2 with the disease. In conclusion, the present study provided no clear evidence for an association between the NOTCH4 gene and schizophrenia in the Japanese population.

Adult↗

PubMed2004

A NOTCH4 association with multiple sclerosis is secondary to HLA-DR*1501.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with supposedly autoimmune features known to be associated with a specific HLA DR-DQ haplotype (DR15, DQ6, or HLDRB1*1501,DRB5*0101,DQA1*0102,DQB1*0602). We have previously reported that the associated haplotype extends to HLA-B and described an independent association with HLA-A alleles in MS. Owing to a complex situation with extensive linkage disequilibria, it is still unclear whether classical HLA genes are responsible or whether associations may be due to other genes in this region. Here, we analyzed an association in MS with the NOTCH4 and TNFalpha (tumor necrosis factor-alpha) genes, located between the HLA-DRB1 gene and the HLA-A gene. For NOTCH4, located 0.4 Mb telomeric to HLA-DRB1, an SNP at position -25 and a trinucleotide repeat were investigated in 181 MS patients, and 180 controls also typed P = 0.027 for HLA-DRB and HLA-A. A modest association was observed (OR = 3.44) with the C-25 allele. However, two-locus analysis revealed that this association was secondary to the classical association with HLA-DRB1. For TNF, located 0.7 Mb telomeric of NOTCH4, SNPs at positions -308 and -238 were studied in the same dataset. We found no association between these TNFalpha gene polymorphisms and MS in this dataset, although there was linkage disequilibrium (LD) between DRB1 and TNF and between HLA-A and TNF. We conclude that alleles of the NOTCH4 and TNFalpha genes are unlikely to be of importance for the susceptibility to MS, although specific alleles of these genes are often carried on the same haplotype as DR15, DQ6.

Alleles↗

PubMed2006

A review and re-evaluation of an association between the NOTCH4 locus and schizophrenia.

This work reviewed all the reports on the NOTCH4 gene in schizophrenia, which have been published since the gene was found to be associated with illness among a British population in 2000. The results from independent studies were inconsistent. Allelic heterogeneity, clinical diagnosis, ethnical backgrounds, and linkage disequilibrium (LD) structures in the human genome may be major reasons for poor replication. A couple of studies suggested that the NOTCH4 gene could play a role in a subgroup of the disease, such as early-onset schizophrenia and negative symptoms. A single study revealed a weak association of the NOTCH4 gene with frontal lobe brain volumes and a strong association with frontal lobe cognitive performance. A meta-analysis showed stronger evidence of the NOTCH4 association in family-based studies than in case-control studies. In a previous study, we found that rs520692, a single nucleotide polymorphism (SNP) at the NOTCH4 locus, was associated with schizophrenia in a Chinese population. In the present study, we applied a large sample size to re-evaluate our initial findings and then confirmed the rs520692 association with illness. The pairwise measures did not show strong LD between paired SNPs although the SNPs tested are located within a 34-kb region, suggesting that LD within the NOTCH4 gene has been broken rapidly by historical recombination in the Chinese population. Taken together, the NOTCH4 gene may be associated with schizophrenia but how the gene contributes to the etiology of the illness needs a further investigation.

Asian People↗