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)

Activating mutations in the genes for fibroblast growth factor receptors 1-3 (FGFR1-3) are responsible for a diverse group of skeletal disorders. In general, mutations in FGFR1 and FGFR2 cause the majority of syndromes involving craniosynostosis, whereas the dwarfing syndromes are largely associated with FGFR3 mutations. Osteoglophonic dysplasia (OD) is a "crossover" disorder that has skeletal phenotypes associated with FGFR1, FGFR2, and FGFR3 mutations. Indeed, patients with OD present with craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as the rhizomelic dwarfism and nonossifying bone lesions that are characteristic of the disorder. We demonstrate here that OD is caused by missense mutations in highly conserved residues comprising the ligand-binding and transmembrane domains of FGFR1, thus defining novel roles for this receptor as a negative regulator of long-bone growth.
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PMID:Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. 1562 20

Fibroblast growth factor receptors (FGFRs) exist as a gene family of 4 membrane bound receptor tyrosine kinases (FGFR1-4) that mediate signals of at least 22 fibroblast growth factors (FGF1-22). FGFs/FGFRs play important roles in multiple biological processes, including mesoderm induction and patterning, cell growth and migration, organ formation and bone growth. Furthermore, it has been shown that missense mutations of FGFR1-3 in human result in, at least, 14 congential bone diseases that are broadly classified into two groups: chondrodysplasia syndromes and craniosynostosis syndromes. The chondrodysplasia affects primarily the skeleton formed through endochondral ossification, resulting short-limbed dwarfisms, while the craniosynostosis affects mainly bones formed through intramembraneous ossification, leading to premature fusion of the craniofacial sutures. Using gene targeting, mouse models mimicking some of these human diseases have been created. Analysis of these mutant mice revealed essential functions of FGFs/FGFRs in skeletal development and maintenance. These models may be beneficial in future studies aimed at developing novel therapeutic strategies for FGFR-related skeletal dysplasias. In this review, we discuss the results of recent studies on FGF receptors to illustrate mechanisms through which the abnormally activated FGF/FGFR signaling results in these diseases.
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PMID:Roles of FGF signaling in skeletal development and human genetic diseases. 1576 77

Mutations in FGFR1 and TWIST1 have been reported to affect the timing of calvarial suture fusion resulting in craniosynostosis and facial abnormalities. We screened nonpathologic populations for genetic polymorphisms that may associate with normal craniofacial variation. We identified 17 single-nucleotide polymorphisms (SNPs) in FGFR1, 6 of which were novel (g.8591855G-->A, g.8593685G-->A, g.8602303C-->T, g.8602475A-->G (p.Ile293Val), g.8605849C-->T, g.8607868G-->A). No SNPs were found in TWIST1. FGFR1 SNP haplotypes were reconstructed for Caucasian, Asian, Australian Aboriginal, and African American populations. All populations shared two linkage disequilibrium blocks, with one haplotype-tag SNP (htSNP) tagging each block. The htSNP g.8592931G-->C was found to have a significant negative correlation with the cephalic index for all populations (R = -0.187, p = 0.036), with larger correlations in Asians and females. This finding is a starting point in the identification of a set of SNPs that can be genotyped to determine both normal and disease craniofacial phenotypes.
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PMID:Linkage disequilibrium analysis identifies an FGFR1 haplotype-tag SNP associated with normal variation in craniofacial shape. 1582 Mar 8

Although many theories have attempted to explain the etiopathogenesis of premature cranial suture fusion, which results in craniosynostosis, recent studies have focused on the role of growth factors and receptors. Using a well-established model of cranial suture biology, the authors developed a novel approach to quantitatively analyze the gene expression profiles of candidate cranial suture growth factors and their receptors. We collected suture mesenchyme and adjacent osteogenic fronts from Sprague-Dawley rats at postnatal days 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 35. RNA was extracted from posterior frontal (PF) and sagittal (SAG) sutures, and reverse transcription-polymerase chain reaction (RT-PCR) was performed for cranial suture candidate cytokines BMP2, BMP3, BMP4, FGF-2, FGFR1, FGFR2, FGFR4, TGF-betaRI, TGF-betaRII, and TGF-betaRIII. The authors confirmed quantitative RT-PCR results with Southern and dot blot analyses. Suture growth factor and receptor expression levels changed significantly with time. Expression levels decreased toward baseline in the SAG suture by day 35. There was a marked difference in FGFR1, FGF-2, TGF-betaRI, and TGF-betaRII expression levels when comparing the fusing PF and nonfusing SAG sutures. Although FGF-2 ligand expression was low, FGF receptor 1 (FGFR1) levels were markedly elevated with a bimodal expression pattern in both PF and SAG similar to that of BMP2, BMP3, and BMP4. Although there were statistically significant differences in TGF-betaRI and TGF-betaRII expression in the PF and SAG sutures, TGF-betaRIII levels were unchanged. The authors report a novel approach to cranial suture growth factor/receptor profiling and confirm their results with standard analytic tools. The data confirm, quantify, and extend the results of previously published studies. By quantifying the gene expression profiles of normal cranial suture biology, we may begin to understand the aberrant growth factor cascades of craniosynostosis and devise targeted therapeutic interventions that can alter the course of this malady.
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PMID:Gene expression profiling in the rat cranial suture. 1591

The Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with uni- or bilateral coronal synostosis and mild limb deformities. It is caused by loss-of-function mutations of the TWIST 1 gene. In an attempt to delineate functional features separating SCS from Muenke's syndrome, we screened patients presenting with coronal suture synostosis for mutations in the TWIST 1 gene, and for the Pro250Arg mutation in FGFR3. Within a total of 124 independent pedigrees, 39 (71 patients) were identified to carry 25 different mutations of TWIST 1 including 14 novel mutations, to which six whole gene deletions were added. The 71 patients were compared with 42 subjects from 24 pedigrees carrying the Pro250Arg mutation in FGFR3 and 65 subjects from 61 pedigrees without a detectable mutation. Classical SCS associated with a TWIST 1 mutation could be separated phenotypically from the Muenke phenotype on the basis of the following features: low-set frontal hairline, gross ptosis of eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and hallux valgus or broad great toe with bifid distal phalanx. Functional differences were even more important: intracranial hypertension as a consequence of early progressive multisutural fusion was a significant problem in SCS only, while mental delay and sensorineural hearing loss were associated with the Muenke's syndrome. Contrary to previous reports, SCS patients with complete loss of one TWIST allele showed normal mental development.
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PMID:Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome. 1625 95

Craniosynostosis is a congenital developmental disorder involving premature fusion of cranial sutures, which results in an abnormal shape of the skull. Significant progress in understanding the molecular basis of this phenotype has been made for a small number of syndromic craniosynostosis forms. Nevertheless, in the majority of the approximately 100 craniosynostosis syndromes and in non-syndromic craniosynostosis the underlying gene defects and pathomechanisms are unknown. Here we report on a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. Three dimensional cranial computer tomography showed fusion of the lambdoid sutures and distal part of the sagittal suture with a gaping anterior fontanelle. Mutations in the genes for FGFR2 and FGFR3 were excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes. SOX6 mutation screening of another 104 craniosynostosis patients revealed one missense mutation leading to the exchange of a highly conserved amino acid (p.D68N) in a single patient and his reportedly healthy mother. The breakpoint on chromosome 9 is located in a region without any known or predicted genes but, interestingly, disrupts patches of evolutionarily highly conserved non-genic sequences and may thus led to dysregulation of flanking genes on chromosome 9 or 11 involved in skull vault development. The present case is one of the very rare reports of an apparently balanced translocation in a patient with syndromic craniosynostosis, and reveals novel candidate genes for craniosynostoses and cranial suture formation.
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PMID:Balanced translocation in a patient with craniosynostosis disrupts the SOX6 gene and an evolutionarily conserved non-transcribed region. 1625 6

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

The Apert syndrome is characterized by craniosynostosis and syndactyly of hands and feet. Although most cases are sporadic, an autosomal dominant mode of inheritance is well documented. Two mutations in the FGFR2 gene (Ser252Trp and Pro253Arg) account for most of the cases. We report a patient with a rare form of Apert syndrome with polydactyly. The proposita has turribrachycephaly. complete syndactyly of 2nd to 5th digits ("mitten hands" and cutaneous fusion of all toes). The X-rays revealed craniosynostosis of the coronal suture and preaxial polydactyly of hands and feet with distal bony fusion. Molecular analysis found a C755G transversion (Ser252Trp) in the FGFR2 gene. Only eight patients with Apert syndrome and preaxial polydactyly have been reported and this is the first case in which molecular diagnosis is available. On the basis of the molecular findings in this patient, polydactyly should be considered part of the spectrum of abnormalities in the Apert syndrome. This assertion would establish the need for a new molecular classification of the acrocephalopolysyndactylies.
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PMID:Apert syndrome with preaxial polydactyly showing the typical mutation Ser252Trp in the FGFR2 gene. 1644 Aug 83

This paper reports a new type of syndromic craniosynostosis that was diagnosed by DNA analysis of the patient's fibroblast growth factor receptor (FGFR) genes. At birth, a male infant had ocular proptosis, a pseudotail, and obstructed respiration. He developed craniosynostosis, craniofacial dysmorphism, hydrocephalus, and bilateral contracture of his elbow joints. His treatment included fronto-orbital advancements and a ventriculoperitoneal shunt. Genetic analysis revealed that he was heterozygous for a missense mutation in exon 9 of the FGFR2 gene that resulted in an amino acid substitution of cysteine for serine at residue 351 (Ser351Cys). Seven cases with this mutation had previously been reported. All had severe craniosynostosis with midface hypoplasia, elbow joint contracture, developmental retardation, and early death.
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PMID:Syndromic craniosynostosis with elbow joint contracture. 1646 81

Saethre-Chotzen syndrome is associated with haploinsufficiency of the basic-helix-loop-helix (bHLH) transcription factor TWIST1 and is characterized by premature closure of the cranial sutures, termed craniosynostosis; however, the mechanisms underlying this defect are unclear. Twist1 has been shown to play both positive and negative roles in mesenchymal specification and differentiation, and here we show that the activity of Twist1 is dependent on its dimer partner. Twist1 forms both homodimers (T/T) and heterodimers with E2A E proteins (T/E) and the relative level of Twist1 to the HLH inhibitor Id proteins determines which dimer forms. On the basis of the expression patterns of Twist1 and Id1 within the cranial sutures, we hypothesized that Twist1 forms homodimers in the osteogenic fronts and T/E heterodimers in the mid-sutures. In support of this hypothesis, we have found that genes regulated by T/T homodimers, such as FGFR2 and periostin, are expressed in the osteogenic fronts, whereas genes regulated by T/E heterodimers, such as thrombospondin-1, are expressed in the mid-sutures. The ratio between these dimers is altered in the sutures of Twist1+/- mice, favoring an increase in homodimers and an expansion of the osteogenic fronts. Of interest, the T/T to T/E ratio is greater in the coronal versus the sagittal suture, and this finding may contribute to making the coronal suture more susceptible to fusion due to TWIST haploinsufficiency. Importantly, we were able to inhibit suture fusion in Twist1+/- mice by modulating the balance between these dimers toward T/E formation, by either increasing the expression of E2A E12 or by decreasing Id expression. Therefore, we have identified dimer partner selection as an important mediator of Twist1 function and provide a mechanistic understanding of craniosynostosis due to TWIST haploinsufficiency.
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PMID:Twist1 dimer selection regulates cranial suture patterning and fusion. 1650 19


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