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)

Achondroplasia, the most common cause of chondrodysplasia in man (1 in 15,000 live births), is a condition of unknown origin characterized by short-limbed dwarfism and macrocephaly. More than 90% of cases are sporadic and there is an increased paternal age at the time of conception of affected individuals, suggesting that de novo mutations are of paternal origin. Affected individuals are fertile and achondroplasia is transmitted as a fully penetrant autosomal dominant trait, accounting for rare familial forms of the disease (10%). In contrast, homozygous achondroplasia is usually lethal in the neonatal period and affects 25% of the offspring of matings between heterozygous achondroplasia parents. The gene responsible for achondroplasia has been mapped to chromosome 4p16.3 (refs 7, 8); the genetic interval encompassing the disease gene contains a member of the fibroblast-growth-factor receptor (FGFR3) family which is expressed in articular chondrocytes. Here we report the finding of recurrent missense mutations in a CpG doublet of the transmembrane domain of the FGFR3 protein (glycine substituted with arginine at residue 380, G380R) in 17 sporadic cases and 6 unrelated familial forms of achondroplasia. We show that the mutant genotype segregates with the disease in these families. Thus it appears that recurrent mutations of a single amino acid in the transmembrane domain of the FGFR3 protein account for all cases (23/23) of achondroplasia in our series.
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PMID:Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. 807 86

Achondroplasia (ACH), the most common cause of chondrodysplasia in man (1 in 15,000 live births), is an autosomal dominant condition of unknown origin characterized by short-limbed dwarfism and macrocephaly. Recently, a gene for ACH has been mapped to chromosome 4p16.3. The genetic interval encompassing the disease gene contains a member of the fibroblast growth factor receptor (FGFR) family which is expressed in articular chondrocytes (FGFR3). We report here recurrent missense mutations, in a CpG doublet of the transmembrane domain of the FGFR3 protein (G380R) in 17 sporadic cases and 6 unrelated familial forms of ACH and show that the mutant genotype segregates with the disease in these families. Thus, it appears that recurrent mutations of a single amino acid in the transmembrane domain of the FGFR3 protein account for all cases (23/23) of achondroplasia in our series.
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PMID:Mutations of the fibroblast growth factor receptor-3 gene in achondroplasia. 874 28

Perlecan, a large, multi-domain, heparan sulfate proteoglycan originally identified in basement membrane, interacts with extracellular matrix proteins, growth factors and receptors, and influences cellular signalling. Perlecan is present in a variety of basement membranes and in other extracellular matrix structures. We have disrupted the gene encoding perlecan (Hspg2) in mice. Approximately 40% of Hspg2-/- mice died at embryonic day (E) 10.5 with defective cephalic development. The remaining Hspg2-/- mice died just after birth with skeletal dysplasia characterized by micromelia with broad and bowed long bones, narrow thorax and craniofacial abnormalities. Only 6% of Hspg2-/- mice developed both exencephaly and chondrodysplasia. Hspg2-/- cartilage showed severe disorganization of the columnar structures of chondrocytes and defective endochondral ossification. Hspg2-/- cartilage matrix contained reduced and disorganized collagen fibrils and glycosaminoglycans, suggesting that perlecan has an important role in matrix structure. In Hspg2-/- cartilage, proliferation of chondrocytes was reduced and the prehypertrophic zone was diminished. The abnormal phenotypes of the Hspg2-/- skeleton are similar to those of thanatophoric dysplasia (TD) type I, which is caused by activating mutations in FGFR3 (refs 7, 8, 9), and to those of Fgfr3 gain-of-function mice. Our findings suggest that these molecules affect similar signalling pathways.
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PMID:Perlecan is essential for cartilage and cephalic development. 1054 53

Both gain-of-function and loss-of-function mutations in fibroblast growth factor receptor 3 (Fgfr3) have revealed unique roles for this receptor during skeletal development. Loss-of-function alleles of Fgfr3 lead to an increase in the size of the hypertrophic zone, delayed closure of the growth plate and the subsequent overgrowth of long bones. Gain-of-function mutations in Fgfr3 have been genetically linked to autosomal dominant dwarfing chondrodysplasia syndromes where both the size and architecture of the epiphyseal growth plate are altered. Analysis of these phenotypes and the biochemical consequences of the mutations in FGFR3 demonstrate that FGFR3-mediated signalling is an essential negative regulator of endochondral ossification.
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PMID:Regulation of chondrocyte growth and differentiation by fibroblast growth factor receptor 3. 1127 88

Gain of function mutations in fibroblast growth factor (FGF) receptors cause chondrodysplasia and craniosynostosis syndromes. The ligands interacting with FGF receptors (FGFRs) in developing bone have remained elusive, and the mechanisms by which FGF signaling regulates endochondral, periosteal, and intramembranous bone growth are not known. Here we show that Fgf18 is expressed in the perichondrium and that mice homozygous for a targeted disruption of Fgf18 exhibit a growth plate phenotype similar to that observed in mice lacking Fgfr3 and an ossification defect at sites that express Fgfr2. Mice lacking either Fgf18 or Fgfr3 exhibited expanded zones of proliferating and hypertrophic chondrocytes and increased chondrocyte proliferation, differentiation, and Indian hedgehog signaling. These data suggest that FGF18 acts as a physiological ligand for FGFR3. In addition, mice lacking Fgf18 display delayed ossification and decreased expression of osteogenic markers, phenotypes not seen in mice lacking Fgfr3. These data demonstrate that FGF18 signals through another FGFR to regulate osteoblast growth. Signaling to multiple FGFRs positions FGF18 to coordinate chondrogenesis in the growth plate with osteogenesis in cortical and trabecular bone.
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PMID:Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. 1193 93

We present a second family with survival to adulthood and dominant transmission of the Torrance-Luton type of platyspondylic chondrodysplasia, and demonstrate the radiographs at different ages together with radiographs and further data of the first family which was published in the Journal of Pediatrics (J Pediatr 136:411-413). Two families are described with survival to adulthood and dominant transmission of the Torrance-Luton type of platyspondylic chondrodysplasia. Although lethality is increased in patients with this disorder, mild expressions of the genetic defect are compatible with survival into adulthood. The heterogeneous group of platyspondylic lethal skeletal dysplasias (PLSD) originally included thanatophoric dysplasias (TD1/2: MIM 187600, 187100) as the most common forms of this condition, as well as TD variants San Diego type (PLSD-SD: MIM 270230) and Torrance-Luton type (PLSD-TL: MIM 151210). Fibroblast growth factor receptor 3 ( FGFR3) gene mutations have been detected in TD1/2 and PLSD-SD. Molecular studies in one of our two families with the Torrance-Luton type did not disclose mutations in the FGFR3 coding region, suggesting that this type of platyspondylic chondrodysplasia is not a thanatophoric dysplasia variant. In contrast to TD1/2 and PLD-SD, the Torrance-Luton type platyspondylic dysplasia is compatible with survival to adulthood.
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PMID:Survival to adulthood and dominant inheritance of platyspondylic skeletal dysplasia, Torrance-Luton type. 1296 Oct 49

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

Gain-of-function mutations in fibroblast growth factor (FGF) receptors result in chondrodysplasia and craniosynostosis syndromes, highlighting the critical role for FGF signaling in skeletal development. Although the FGFRs involved in skeletal development have been well characterized, only a single FGF ligand, FGF18, has been identified that regulates skeletal development during embryogenesis. Here we identify Fgf9 as a second FGF ligand that is critical for skeletal development. We show that Fgf9 is expressed in the proximity of developing skeletal elements and that Fgf9-deficient mice exhibit rhizomelia (a disproportionate shortening of proximal skeletal elements), which is a prominent feature of patients with FGFR3-induced chondrodysplasia syndromes. Although Fgf9 is expressed in the apical ectodermal ridge in the limb bud, we demonstrate that the Fgf9-/- limb phenotype results from loss of FGF9 functions after formation of the mesenchymal condensation. In developing stylopod elements, FGF9 promotes chondrocyte hypertrophy at early stages and regulates vascularization of the growth plate and osteogenesis at later stages of skeletal development.
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PMID:FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. 1754 91

The association of dentinogenesis imperfecta (DI) with a distinct form of chondrodysplasia in a boy was reported by Goldblatt et al. [1991; Am J Med Genet 39:170-172] and has been given the name of Goldblatt syndrome or odontochondrodysplasia (ODCD; OMIM#184260). Since the original description, only four further individuals have been reported (one sib pair and two unrelated cases). We report on an additional six individuals, including a second sib pair (brother and sister), with clinical and radiographic features that cluster and thus confirm the nosologic status of this entity. The main radiographic features are congenital platyspondyly with coronal clefts, severe metaphyseal changes particularly of the hands, wrists, and knees, mesomelic limb shortening, and coxa valga. The main physical signs are short stature, joint laxity, narrow chest, scoliosis, and DI. This combination of clinical and radiographic findings allows clear recognition of this syndrome in early childhood. Of note, the signs that are present in the newborn period are not entirely specific and the differential diagnosis includes spondylometaphyseal dysplasia (SMD) Sedaghatian type or platyspondylic lethal dysplasia (PSLD) Torrance type. The occurrence of two sib pairs in a group of only 11 patients suggests an autosomal recessive inheritance pattern. Overmodification of cartilage-extracted collagen 2 has been reported in two sibs, but mutation analysis of COL2A1 as well as of COMP, FGFR3, RMRP, and SBDS in one or more patients have given negative results, and the molecular etiology is as yet unknown.
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PMID:Clinical and radiographic delineation of odontochondrodysplasia. 1824 Oct 73

The lack of beta1 integrins on chondrocytes leads to severe chondrodysplasia associated with high mortality rate around birth. To assess the impact of beta1 integrin-mediated cell-matrix interactions on the function of adult knee joints, we conditionally deleted the beta1 integrin gene in early limb mesenchyme using the Prx1-cre transgene. Mutant mice developed short limbed dwarfism and had joint defects due to beta1 integrin deficiency in articular regions. The articular cartilage (AC) was structurally disorganized, accompanied by accelerated terminal differentiation, altered shape, and disrupted actin cytoskeleton of the chondrocytes. Defects in chondrocyte proliferation, cytokinesis, and survival resulted in hypocellularity. However, no significant differences in cartilage erosion, in the expression of matrix-degrading proteases, or in the exposure of aggrecan and collagen II cleavage neoepitopes were observed between control and mutant AC. We found no evidence for disturbed activation of MAPKs (ERK1/2, p38, and JNK) in vivo. Furthermore, fibronectin fragment-stimulated ERK activation and MMP-13 expression were indistinguishable in control and mutant femoral head explants. The mutant synovium was hyperplastic and frequently underwent chondrogenic differentiation. beta1-null synoviocytes showed increased proliferation and phospho-focal adhesion kinase expression. Taken together, deletion of beta1 integrins in the limb bud results in multiple abnormalities of the knee joints; however, it does not accelerate AC destruction, perturb cartilage metabolism, or influence intracellular MAPK signaling pathways.
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PMID:Beta1 integrin deficiency results in multiple abnormalities of the knee joint. 1958 17


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