Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enlargement of the skull vault occurs by appositional growth at the fibrous joints between the bones, termed cranial sutures. Relatively little is known about the developmental biology of this process, but genetically determined disorders of premature cranial suture fusion (craniosynostosis) provide one route to the identification of some of the key molecules involved. Mutations of the MSX2, FGFR1, FGFR2, FGFR3 and TWIST genes yield new insights, both into normal and abnormal cranial suture biogenesis and into problems of broad interest, such as the conservation of molecular pathways in development, and mechanisms of mutation and dominance.
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PMID:Craniosynostosis: genes and mechanisms. 930 Jun 56

This article reviews recent molecular genetic findings in autosomal dominant craniosynostotic syndromes. A mutation in the homeotic gene MSX2 was the first genetic defect identified in an autosomal dominant primary craniosynostosis, i.e. in craniosynostosis type 2 (Boston type). In the more common syndromes of Crouzon, Pfeiffer, Jackson-Weiss, and Apert, mutations were found in the gene coding for fibroblast growth factor receptor (FGFR) 2. Less frequently, mutations are observed in FGFR1 and FGFR3 in some cases of Crouzon and Pfeiffer syndrome. The mutations identified in FGFR2 are located in exons 5 and 7 of the gene that code for immunoglobulin (Ig)-like chain III and the region linking Ig II and Ig III of the receptor. These domains of the receptor are important for ligand binding. Apart from Apert syndrome, identical mutations are found in the clinically distinct syndromes of Crouzon, Pfeiffer, and Jackson-Weiss. Furthermore, the same gene defect can result in a highly variable phenotype even within one family. Therefore, the clinically distinct craniosynostotic syndromes are extremes of a spectrum of craniofacial abnormalities and not nosologic entities. In Saethre-Chotzen syndrome, the gene coding for transcription factor TWIST is mutated. The disease genes identified in craniosynostotic syndromes to date either regulate transcription or are required for signal transduction and play a central role in the development of the calvarial sutures.
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PMID:Molecular genetics of craniosynostotic syndromes. 934 2

We describe a consanguineous family of Pakistani origin with five sibs, three of whom were affected by craniosynostosis of variable presentation. In addition, they had other congenital abnormalities principally affecting neurological, ocular, and limb development. We provide linkage evidence using intragenic and flanking microsatellite markers suggesting that the disease in this family was not caused by a mutation in one of the known craniosynostosis loci (FGFR1, FGFR2, FGFR3, MSX2, TWIST). Given the clinical novelty and parental consanguinity, we hypothesise that the affected individuals were autozygous for a recessively inherited mutation, at a novel locus, predisposing to craniosynostosis.
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PMID:Newly recognised craniosynostosis syndrome that does not map to known disease loci. 1107 86

Many genetically determined craniosynostosis syndromes feature limb anomalies, implying that pathways of cranial suture and limb morphogenesis share some identical components. Identification of heterozygous mutations in FGFR1, FGFR2, FGFR3, TWIST and MSX2 in craniosynostosis has focused particular attention on these genes. Here we explore two themes: use of clinical/molecular analysis to provide new clues to pathophysiology and the contrasting effects of loss- and gain-of-function mutations. Apert syndrome is a severe craniosynostosis/syndactyly disorder usually caused by specific substitutions (Ser252Trp or Pro253Arg) in FGFR2. The relative severity of cranial and limb malformations varies in opposite directions for the two mutations, suggesting that these phenotypes arise by different mechanisms. Clinical and biochemical evidence supports a model in which alternative splice forms of FGFR2 mediate these distinct effects. Pro-->Arg substitutions equivalent the Pro253Arg/FGFR2 mutation occur in both FGFR1 and FGFR3, and are also associated with craniosynostosis. This suggests a common pathological mechanism, whereby enhanced affinity for a limited repertoire of tissue-specific ligand(s) excessively prolongs signalling in the cranial suture. The first MSX2 mutation in craniosynostosis was described in 1993 but this remains the only example. We have recently identified three MSX2 mutations associated with a different cranial phenotype, parietal foramina. DNA binding studies show that the craniosynostosis and parietal foramina arise from gain and loss of function, respectively.
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PMID:Craniosynostosis and related limb anomalies. 1127 76

We have investigated the role of FGFs in the control of programmed cell death during limb development by analyzing the effects of increasing and blocking FGF signaling in the avian limb bud. BMPs are currently considered as the signals responsible for cell death. Here we show that FGF signaling is also necessary for apoptosis and that the establishment of the areas of cell death is regulated by the convergence of FGF- and BMP-mediated signaling pathways. As previously demonstrated, cell death is inhibited for short intervals (12 hours) after administration of FGFs. However, this initial inhibition is followed (24 hours) by a dramatic increase in cell death, which can be abolished by treatments with a BMP antagonist (Noggin or Gremlin). Conversely, blockage of FGF signaling by applying a specific FGF-inhibitor (SU5402) into the interdigital regions inhibits both physiological cell death and that mediated by exogenous BMPs. Furthermore, FGF receptors 1, 2 and 3 are expressed in the autopodial mesoderm during the regression of the interdigital tissue, and the expression of FGFR3 in the interdigital regions is regulated by FGFs and BMPs in the same fashion as apopotosis. Together our findings indicate that, in the absence of FGF signaling BMPs are not sufficient to trigger apoptosis in the developing limb. Although we provide evidence for a positive influence of FGFs on BMP gene expression, the physiological implication of FGFs in apoptosis appears to result from their requirement for the expression of genes of the apoptotic cascade. We have identified MSX2 and Snail as candidate genes associated with apoptosis the expression of which requires the combined action of FGFs and BMPs.
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PMID:Role of FGFs in the control of programmed cell death during limb development. 1149 29

Craniosynostosis caused by genetic factors includes a heterogeneous group of over 100 syndromes, most with autosomal dominant inheritance. Mutations in five genes (FGFR1-, -2, -3, TWIST, and MSX2) causing craniosynostosis as the main clinical feature were described. In most of these conditions, there are also limb malformations. We report a two-generation kindred segregating microcornea, optic nerve alterations and cataract since childhood, craniosynostosis, and distal limb alterations, with a great clinical intrafamilial variability. The ophthalmological problems here described seem to be unique to this genealogy while similar feet alterations were apparently only described in two other affected siblings with acro-cranial-facial dysostosis syndrome (ADS). However, ADS has an autosomal recessive inheritance instead of the dominant pattern of the present genealogy. The candidate exons of the five genes previously mentioned were tested through sequencing analysis presenting normal results in all cases. Therefore, clinical and laboratory analyses in our patients suggest that their phenotype represents a new syndrome very likely caused by mutation in a gene different from those studied.
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PMID:Craniosynostosis associated with ocular and distal limb defects is very likely caused by mutations in a gene different from FGFR, TWIST, and MSX2. 1240 13

The development and growth of the skull is a co-ordinated process involving many different tissues that interact with each other to form a complex end result. When normal development is disrupted, debilitating pathological conditions, such as craniosynostosis (premature calvarial suture fusion) and cleidocranial dysplasia (delayed suture closure), can result. It is known that mutations in the fibroblast growth factor receptors 1, 2, and 3(FGFR1, 2, and 3), as well as the transcription factors MSX2 and TWIST cause craniosynostosis, and that mutations in the transcription factor RUNX2 (CBFA1) cause cleidocranial dysplasia. However, relatively little is known about the development of the calvaria: where and when these genes are active during normal calvarial development, how these genes may interact in the developing calvaria, and the disturbances that may occur to cause these disorders. In this work an attempt has been made to address some of these questions from a basic biological perspective. The expression patterns of the above-mentioned genes in the developing mouse skull are detailed. The microdissection and in vitro culture techniques have begun the task of identifying Fgfrs, Msx2, and Twist interacting in intricate signalling pathways that if disrupted could lead to craniosynostosis.
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PMID:Molecular mechanisms in calvarial bone and suture development, and their relation to craniosynostosis. 1273 12

The activity of beta-catenin (beta-cat), a key component of the Wnt signaling pathway, is deregulated in about 40% of ovarian endometrioid adenocarcinomas (OEAs), usually as a result of CTNNB1 gene mutations. The function of beta-cat in neoplastic transformation is dependent on T-cell factor (TCF) transcription factors, but specific genes activated by the interaction of beta-cat with TCFs in OEAs and other cancers with Wnt pathway defects are largely unclear. As a strategy to identify beta-cat/TCF transcriptional targets likely to contribute to OEA pathogenesis, we used oligonucleotide microarrays to compare gene expression in primary OEAs with mutational defects in beta-cat regulation (n = 11) to OEAs with intact regulation of beta-cat activity (n = 17). Both hierarchical clustering and principal component analysis based on global gene expression distinguished beta-cat-defective tumors from those with intact beta-cat regulation. We identified 81 potential beta-cat/TCF targets by selecting genes with at least 2-fold increased expression in beta-cat-defective versus beta-cat regulation-intact tumors and significance in a t test (P < 0.05). Seven of the 81 genes have been previously reported as Wnt/beta-cat pathway targets (i.e., BMP4, CCND1, CD44, FGF9, EPHB3, MMP7, and MSX2). Differential expression of several known and candidate target genes in the OEAs was confirmed. For the candidate target genes CST1 and EDN3, reporter and chromatin immunoprecipitation assays directly implicated beta-cat and TCF in their regulation. Analysis of presumptive regulatory elements in 67 of the 81 candidate genes for which complete genomic sequence data were available revealed an apparent difference in the location and abundance of consensus TCF-binding sites compared with the patterns seen in control genes. Our findings imply that analysis of gene expression profiling data from primary tumor samples annotated with detailed molecular information may be a powerful approach to identify key downstream targets of signaling pathways defective in cancer cells.
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PMID:Novel candidate targets of beta-catenin/T-cell factor signaling identified by gene expression profiling of ovarian endometrioid adenocarcinomas. 1278 98

The mammalian skull vault is constructed principally from five bones: the paired frontals and parietals, and the unpaired interparietal. These bones abut at sutures, where most growth of the skull vault takes place. Sutural growth involves maintenance of a population of proliferating osteoprogenitor cells which differentiate into bone matrix-secreting osteoblasts. Sustained function of the sutures as growth centres is essential for continuous expansion of the skull vault to accommodate the growing brain. Craniosynostosis, the premature fusion of the cranial sutures, occurs in 1 in 2500 children and often presents challenging clinical problems. Until a dozen years ago, little was known about the causes of craniosynostosis but the discovery of mutations in the MSX2, FGFR1, FGFR2, FGFR3, TWIST1 and EFNB1 genes in both syndromic and non-syndromic cases has led to considerable insights into the aetiology, classification and developmental pathology of these disorders. Investigations of the biological roles of these genes in cranial development and growth have been carried out in normal and mutant mice, elucidating their individual and interdependent roles in normal sutures and in sutures undergoing synostosis. Mouse studies have also revealed a significant correspondence between the neural crest-mesoderm boundary in the early embryonic head and the position of cranial sutures, suggesting roles for tissue interaction in suture formation, including initiation of the signalling system that characterizes the functionally active suture.
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PMID:Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies. 1631 97

Bone and cartilage and their disorders are addressed under the following headings: functions of bone; normal and abnormal bone remodeling; osteopetrosis and osteoporosis; epithelial-mesenchymal interaction, condensation and differentiation; osteoblasts, markers of bone formation, osteoclasts, components of bone, and pathology of bone; chondroblasts, markers of cartilage formation, secondary cartilage, components of cartilage, and pathology of cartilage; intramembranous and endochondral bone formation; RUNX genes and cleidocranial dysplasia (CCD); osterix; histone deacetylase 4 and Runx2; Ligand to receptor activator of NFkappaB (RANKL), RANK, osteoprotegerin, and osteoimmunology; WNT signaling, LRP5 mutations, and beta-catenin; the role of leptin in bone remodeling; collagens, collagenopathies, and osteogenesis imperfecta; FGFs/FGFRs, FGFR3 skeletal dysplasias, craniosynostosis, and other disorders; short limb chondrodysplasias; molecular control of the growth plate in endochondral bone formation and genetic disorders of IHH and PTHR1; ANKH, craniometaphyseal dysplasia, and chondrocalcinosis; transforming growth factor beta, Camurati-Engelmann disease (CED), and Marfan syndrome, types I and II; an ACVR1 mutation and fibrodysplasia ossificans progressiva; MSX1 and MSX2: biology, mutations, and associated disorders; G protein, activation of adenylyl cyclase, GNAS1 mutations, McCune-Albright syndrome, fibrous dysplasia, and Albright hereditary osteodystrophy; FLNA and associated disorders; and morphological development of teeth and their genetic mutations.
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PMID:The new bone biology: pathologic, molecular, and clinical correlates. 1710 47


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