Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Knobloch syndrome (KS) is a rare disease characterized by severe ocular alterations, including vitreoretinal degeneration associated with retinal detachment and occipital scalp defect. The responsible gene, COL18A1, has been mapped to 21q22.3, and, on the basis of the analysis of one family, we have demonstrated that a mutation affecting only one of the three COL18A1 isoforms causes this phenotype. We report here the results of the screening of both the entire coding region and the exon-intron boundaries of the COL18A1 gene (which includes 43 exons), in eight unrelated patients with KS. Besides 20 polymorphic changes, we identified 6 different pathogenic changes in both alleles of five unrelated patients with KS (three compound heterozygotes and two homozygotes). All are truncating mutations leading to deficiency of one or all collagen XVIII isoforms and endostatin. We have verified that, in exon 41, the deletion c3514-3515delCT, found in three unrelated alleles, is embedded in different haplotypes, suggesting that this mutation has occurred more than once. In addition, our results provide evidence of nonallelic genetic heterogeneity in KS. We also show that the longest human isoform (NC11-728) is expressed in several tissues (including the human eye) and that lack of either the short variant or all of the collagen XVIII isoforms causes similar phenotypes but that those patients who lack all forms present more-severe ocular alterations. Despite the small sample size, we found low endostatin plasma levels in those patients with mutations leading to deficiency of all isoforms; in addition, it seems that absence of all collagen XVIII isoforms causes predisposition to epilepsy.
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PMID:Molecular analysis of collagen XVIII reveals novel mutations, presence of a third isoform, and possible genetic heterogeneity in Knobloch syndrome. 1241 12

Endostatin, located in the NC1 domain of the collagen XVIII, is believed to inhibit the migration and proliferation of endothelial cells (Fed. Am. Soc. Exp. Biol. J. 15 (2001) 1044) and to play a role in axon guidance in Caenorhabditis elegans (J. Cell Biol. 152 (2001) 1219). Zebrafish is an attractive vertebrate model to determine the role of endostatin and the entire molecule of collagen XVIII during vertebrate development. Therefore, we have investigated the expression pattern of COL18A1 in zebrafish embryos from the segmentation to the hatching period stages.
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PMID:Sequence and embryonic expression of collagen XVIII NC1 domain (endostatin) in the zebrafish. 1279 84

Knobloch syndrome (KNO) is an autosomal recessive disorder characterized by high myopia, vitreoretinal degeneration with retinal detachment, and congenital encephalocele. Pathogenic mutations in the COL18A1 gene on 21q22.3 were recently identified in KNO families. Analysis of two unrelated KNO families from Hungary and New Zealand allowed us to confirm the involvement of COL18A1 in the pathogenesis of KNO and to demonstrate the existence of genetic heterogeneity. Two COL18A1 mutations were identified in the Hungarian family: a 1-bp insertion causing a frameshift and a premature in-frame stop codon and an amino acid substitution. This missense variant is located in a conserved amino acid of endostatin, a cleavage product of the carboxy-terminal domain of collagen alpha 1 XVIII. D1437N (D104N in endostatin) likely represents a pathogenic mutation, as we show that the endostatin N104 mutant is impaired in its affinity towards laminin. Linkage to the COL18A1 locus was excluded in the New Zealand family, providing evidence for the existence of a second KNO locus. We named the second unmapped locus for Knobloch syndrome KNO2. Mutation analysis excluded COL15A1, a member of the multiplexin collagen subfamily similar to COL18A1, as being responsible for KNO2.
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PMID:Knobloch syndrome: novel mutations in COL18A1, evidence for genetic heterogeneity, and a functionally impaired polymorphism in endostatin. 1571 16

Collagen XVIII is a component of basement membranes (BMs) with the structural properties of both a collagen and a proteoglycan. Proteolytic cleavage within its C-terminal domain releases a fragment, endostatin, which has been reported to have anti-angiogenesis effects. Molecular studies demonstrated binding of the endostatin domain to heparan sulfate and to BM components like laminin and perlecan, but the functional role of these interactions in vivo remains unknown. Insights into the physiological function of collagen XVIII/endostatin have recently been obtained through the identification of inactivating mutations in the human collagen XVIII/endostatin gene (COL18A1) in patients with Knobloch syndrome, characterized by age-dependent vitreoretinal degeneration and occipital encephalocele. That collagen XVIII/endostatin has an essential role in ocular development and the maintenance of visual function is further demonstrated by the ocular abnormalities seen in mice lacking collagen XVIII/endostatin. Age-dependent loss of vision in these mutant mice is associated with pathological accumulation of deposits under the retinal pigment epithelium, as seen in early stages of age-related macular degeneration in humans. In addition, recent evidence suggests that lack of collagen XVIII/endostatin predisposes to hydrocephalus formation. These recent findings demonstrate an important role for collagen XVIII/endostatin in cell-matrix interactions in certain tissues that may be compensated for in other tissues expressing this collagen.
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PMID:Physiological role of collagen XVIII and endostatin. 1585 86

The transcriptional activity of the p53 protein is central to its role in tumor suppression. Identification of the complete repertoire of p53-regulated genes is critical for dissecting the complexity of the p53 network. Although several different approaches have been used to characterize the p53 genetic program, we still lack a comprehensive molecular understanding of how p53 prevents cancer. Using a computational approach, we generated a genome-wide map of p53 binding sites (p53BS) to identify novel p53 target genes. We show that the presence of nearby p53BS can identify new proapoptotic members of the Bcl2 family. We show that p53 binds to p53BS identified in the BCL-G/BCL2L14 gene and that induction of this gene contributes to p53-mediated apoptosis. We found that p53 activates the COL18A1 gene encoding the precursor for the antiangiogenic factor endostatin. We also show that p53 up-regulates the MAP4K4 gene and activates the c-Jun NH2-terminal kinase (JNK) pathway to drive apoptosis. Thus, unbiased mapping of the genomic landscape of p53BS provides a systematic and complementary approach to identify novel factors and connections in the p53 genetic network. Our study illustrates how systematic genomic approaches can identify binding sites that are functionally relevant for a p53 transcriptional program. The genetic link among p53, antiangiogenic factors, and the JNK signaling pathway adds new dimensions to understanding p53 function in highly connected genetic networks.
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PMID:A genomic map of p53 binding sites identifies novel p53 targets involved in an apoptotic network. 1595 53

We investigated the influence of the polymorphism D104N of the COL18A1 gene, encoding endostatin, on the occurrence of sporadic breast cancer in 181 patients and 448 controls. The homozygous 104NN polymorphism was found in five patients but was absent in controls (2.8% vs 0.0%; P = 0.002). Individuals with this genotype had a significantly increased risk for disease. Our results suggest, for the first time, that the homozygous 104NN polymorphism, even at low frequency, constitutes an important inherited determinant of the disease.
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PMID:A high risk of occurrence of sporadic breast cancer in individuals with the 104NN polymorphism of the COL18A1 gene. 1680 76

Knobloch syndrome (KNO) is an autosomal recessive disorder characterized by ocular abnormalities (myopia and retinal detachment) and occipital encephalocele. The syndrome is clinically and genetically heterogeneous (KNO1, KNO2). Previously germline mutations in COL18A1 (21q22.3) were detected in some families, but in other kindreds linkage to COL18A1 was excluded. We ascertained a large consanguineous family with high myopia, vitreoretinal degeneration and occipital scalp defect with autosomal recessive mode of inheritance. Due to the overlapping clinical presentation of this family with Knobloch syndrome we propose this phenotype as a type III variant of KS (KNO3). A genome wide linkage study using microsatellite markers at 10-20 cM interval revealed linkage to 17q11.2 with a maximum LOD scores 3.40 (theta = 0.00) for markers D17S1307 and D17S1166. Fine mapping defined a 2.67 cM disease region between D17S1307 and D17S798. Mutation analysis of three candidate genes (UNC119, MYO1D, and RAB11FIP4) within the disease region did not identify any disease-associated mutation in affected individuals.
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PMID:Mapping of a novel type III variant of Knobloch syndrome (KNO3) to chromosome 17q11.2. 1797 99

Collagen XVIII can generate two fragments, NC11-728 containing a frizzled motif which possibly acts in Wnt signaling and Endostatin, which is cleaved from the NC1 and is a potent inhibitor of angiogenesis. Collagen XVIII and Wnt signaling have recently been associated with adipogenic differentiation and obesity in some animal models, but not in humans. In the present report, we have shown that COL18A1 expression increases during human adipogenic differentiation. We also tested if polymorphisms in the Frizzled (c.1136C>T; Thr379Met) and Endostatin (c.4349G>A; Asp1437Asn) regions contribute towards susceptibility to obesity in patients with type 2 diabetes (113 obese, BMI > or =30; 232 non-obese, BMI < 30) of European ancestry. No evidence of association was observed between the allele c.4349G>A and obesity, but we observed a significantly higher frequency of homozygotes c.1136TT in obese (19.5%) than in non-obese individuals (10.9%) [P = 0.02; OR = 2.0 (95%CI: 1.07-3.73)], suggesting that the allele c.1136T is associated to obesity in a recessive model. This genotype, after controlling for cholesterol, LDL cholesterol, and triglycerides, was independently associated with obesity (P = 0.048), and increases the chance of obesity in 2.8 times. Therefore, our data suggest the involvement of collagen XVIII in human adipogenesis and susceptibility to obesity.
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PMID:COL18A1 is highly expressed during human adipocyte differentiation and the SNP c.1136C > T in its "frizzled" motif is associated with obesity in diabetes type 2 patients. 1834 85

Type XVIII collagen is a component of basement membranes, and expressed prominently in the eye, blood vessels, liver, and the central nervous system. Homozygous mutations in COL18A1 lead to Knobloch Syndrome, characterized by ocular defects and occipital encephalocele. However, relatively little has been described on the role of type XVIII collagen in development, and nothing is known about the regulation of its tissue-specific expression pattern. We have used zebrafish transgenesis to identify and characterize cis-regulatory sequences controlling expression of the human gene. Candidate enhancers were selected from non-coding sequence associated with COL18A1 based on sequence conservation among mammals. Although these displayed no overt conservation with orthologous zebrafish sequences, four regions nonetheless acted as tissue-specific transcriptional enhancers in the zebrafish embryo, and together recapitulated the major aspects of col18a1 expression. Additional post-hoc computational analysis on positive enhancer sequences revealed alignments between mammalian and teleost sequences, which we hypothesize predict the corresponding zebrafish enhancers; for one of these, we demonstrate functional overlap with the orthologous human enhancer sequence. Our results provide important insight into the biological function and regulation of COL18A1, and point to additional sequences that may contribute to complex diseases involving COL18A1. More generally, we show that combining functional data with targeted analyses for phylogenetic conservation can reveal conserved cis-regulatory elements in the large number of cases where computational alignment alone falls short.
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PMID:Functionally conserved cis-regulatory elements of COL18A1 identified through zebrafish transgenesis. 1989 2

Rhabdoid tumors (RT) are aggressive tumors characterized by genetic loss of SMARCB1 (SNF5, INI-1), a component of the SWI/SNF chromatin remodeling complex. No effective treatment is currently available. This study seeks to shed light on the SMARCB1-mediated pathogenesis of RT and to discover potential therapeutic targets. Global gene expression of 10 RT was compared with 12 cellular mesoblastic nephromas, 16 clear cell sarcomas of the kidney, and 15 Wilms tumors. In all, 114 top genes were differentially expressed in RT (P<0.001, fold change >2 or <0.5). Among these were downregulation of SMARCB1 and genes previously associated with SMARCB1 (ATP1B1, PTN, DOCK4, NQO1, PLOD1, PTP4A2, PTPRK); 28/114 top differentially expressed genes were involved with neural or neural crest development and were all sharply downregulated. This was confirmed by Gene Set Enrichment Analysis (GSEA). Neural and neural crest stem cell marker proteins SOX10, ID3, CD133, and Musashi were negative by immunohistochemistry, whereas Nestin was positive. Decreased expression of CDKN1A, CDKN1B, CDKN1C, CDKN2A, and CCND1 was identified, while MYC-C was upregulated. GSEA of independent gene sets associated with bivalent histone modification and polycomb group targets in embryonic stem cells showed significant negative enrichment in RT. Several differentially expressed genes were associated with tumor suppression, invasion, and metastasis, including SPP1 (osteopontin), COL18A1 (endostatin), PTPRK, and DOCK4. We conclude that RTs arise within early progenitor cells during a critical developmental window in which loss of SMARCB1 directly results in repression of neural development, loss of cyclin-dependent kinase inhibition, and trithorax/polycomb dysregulation.
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PMID:Rhabdoid tumor: gene expression clues to pathogenesis and potential therapeutic targets. 2021 51


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