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)

We describe an apparently unique disorder, Fronto-Ocular syndrome, present in a mother and her two daughters, and comprising trigonocephaly due to coronal and metopic craniosynostosis, ocular hypotelorism, ocular proptosis and ptosis, epicanthal folds, hypoplastic supraorbital ridges, elevated nasal bridge, thin philtrum, high-arched palate and a narrow bifrontal region. Both daughters have glabellar capillary hemangiomas, a congenital heart defect and mild developmental disabilities. Review of the literature failed to disclose any syndrome with similar findings. It is likely that this disorder represents an autosomal dominant condition, that arose as a new mutation in the mother. Mutational analysis of fibroblast growth factor receptor (FGFR) 1 and FGFR2 failed to identify the molecular basis of the disorder.
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PMID:Fronto-ocular syndrome: newly recognized trigonocephaly syndrome. 1086 8

Mutations in the fibroblast growth factor receptor 1, 2 and 3 (FGFR1, -2 and -3) and TWIST genes have been identified in several syndromic forms of craniosynostosis. There remains, however, a significant number of patients with non-syndromic craniosynostosis in whom no genetic cause can be identified. We describe a novel heterozygous mutation of FGFR2 (943G --> T, encoding the amino acid substitution Ala315Ser) in a girl with non-syndromic unicoronal craniosynostosis. The mutation is also present in her mother and her maternal grandfather who have mild facial asymmetry but do not have craniosynostosis. None of these individuals has the Crouzonoid appearance typically associated with FGFR2 mutations. However, the obstetric history revealed that the proband was in persistent breech presentation in utero and was delivered by Caesarean section, at which time compression of the skull was apparent. We propose that this particular FGFR2 mutation only confers a predisposition to craniosynostosis and that an additional environmental insult (in this case foetal head constraint associated with breech position) is necessary for craniosynostosis to occur. To our knowledge, this is the first report of an interaction between a weakly pathogenic mutation and intrauterine constraint, leading to craniosynostosis.
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PMID:A novel mutation, Ala315Ser, in FGFR2: a gene-environment interaction leading to craniosynostosis? 1095 18

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

Craniosynostosis syndromes are autosomal dominant human skeletal diseases that result from various mutations in fibroblast growth factor receptor genes (Fgfrs). Apert syndrome (AS) is one of the most severe craniosynostosis syndromes and is associated with severe syndactyly of the hands and feet and with central nervous system malformations. AS is caused by specific missense mutations in one of two adjacent amino acid residues (S252W or P253R) in the highly conserved region linking Ig-like domains II and III of FGFR2. Here we demonstrate that these mutations break one of the cardinal rules governing ligand specificity of FGFR2. We show that the S252W mutation allows the mesenchymal splice form of FGFR2 (FGFR2c) to bind and to be activated by the mesenchymally expressed ligands FGF7 or FGF10 and the epithelial splice form of FGFR2 (FGFR2b) to be activated by FGF2, FGF6, and FGF9. These data demonstrate loss of ligand specificity of FGFR2 with retained ligand dependence for receptor activation. These data suggest that the severe phenotypes of AS likely result from ectopic ligand-dependent activation of FGFR2.
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PMID:Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome. 1112 Oct 55

A cohort of 36 unrelated German patients with craniosynostosis syndromes of the Crouzon and Pfeiffer type were analyzed for FGFR mutations. Mutations in FGFR2 were identified in 25 Crouzon and 5 Pfeiffer syndrome patients, whereas no sequence alterations were found in the remaining patients, even after screening of the relevant parts of FGFR1, FGFR3, and TWIST. Mutations in FGFR2 clustered at two critical cysteine residues, 278 and 342, which were involved in 18 of 30 cases (60%). These two mutational hot spots, therefore, are prime targets for an efficient mutation-screening strategy. The spectrum of mutations overlapped the two syndromes and thus reflected the phenotypic similarities observed in both patient groups. In 21 families, the origin of the mutation could be traced by analyzing parents and relatives. Eleven mutations arose de novo, indicating a high mutation rate for FGFR2. In the 10 familial cases, the clinical presentation varied considerably within the pedigree, but both syndromes "bred true," i.e., a Pfeiffer syndrome phenotype was never observed in a Crouzon syndrome family and vice versa.
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PMID:Clustering of FGFR2 gene mutations inpatients with Pfeiffer and Crouzon syndromes (FGFR2-associated craniosynostoses). 1117 45

Non-syndromic trigonocephaly is a heterogeneous entity; in most cases the origin is unknown. Rare cases with autosomal dominant and recessive inheritance exist. Here the mutational screening of ten patients in the FGFR1, 2, and 3 genes and the TWIST gene causative of autosomal dominant craniosynostosis syndromes was reported. In one girl an unusual FGFR1 mutation was found.
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PMID:An unusual FGFR1 mutation (fibroblast growth factor receptor 1 mutation) in a girl with non-syndromic trigonocephaly. 1117 46

Cherubism is a rare autosomal dominant fibro-osseous disorder that affects almost exclusively maxilla and mandible. Extracranial skeletal involvement is rare. We report on three affected males in three generations. The youngest affected relative was examined at age 4 months. He also had craniosynostosis. His affected father and grandfather had cherubism and clubbing of the fingers. Cherubism was mapped to region 4p16. Because of the associated cranio-synostosis, we excluded the FGFR3 gene as a candidate gene for cherubism.
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PMID:Craniosynostosis in cherubism. 1118 85

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

Autosomal dominant disorders of skeletal and cranial development have been linked to fibroblast growth factor receptor (FGFR) 2 and FGFR3. Here we report two identical mutations in FGFR2 that cause craniosynostosis syndromes, Crouzon, Apert, and Pfeiffer in gastric carcinoma. A missense mutation (Ser267Pro) in exon IIIa and a splice site mutation (940-2A-->G) in exon IIIc were detected in gastric cancer patients. Interestingly, these heterozygous somatic mutations are identical to the germinal activating mutations in FGFR2 reported previously in craniosynostosis syndromes. In addition, the two novel mutations of FGFR3 in colorectal carcinomas were identified. All identified mutations occurred at highly conserved sequences, not only in the FGFR family of molecules, but also throughout evolution and clustered in the immunoglobulin-like loop-III domain, highlighting the functional importance of this domain. Our results indicate that FGFR2 and FGFR3, in addition to their potential role in skeletal dysplasias, play an important role in tumorigenesis.
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PMID:Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. 1132 14

The cranial neural crest gives rise to most of the skeletal tissues of the skull. Matrix-mediated tissue interactions have been implicated in the skeletogenic differentiation of crest cells, but little is known of the role that growth factors might play in this process. The discovery that mutations in fibroblast growth factor receptors (FGFRs) cause the major craniosynostosis syndromes implicates FGF-mediated signalling in the skeletogenic differentiation of the cranial neural crest. We now show that, in vitro, mesencephalic neural crest cells respond to exogenous FGF2 in a dose-dependent manner, with 0.1 and 1 ng/ml causing enhanced proliferation, and 10 ng/ml inducing cartilage differentiation. In longer-term cultures, both endochondral and membrane bone are formed. FGFR1, FGFR2 and FGFR3 are all detectable by immunohistochemistry in the mesencephalic region, with particularly intense expression at the apices of the neural folds from which the neural crest arises. FGFRs are also expressed by subpopulations of neural crest cells in culture. Collectively, these findings suggest that FGFs are involved in the skeletogenic differentiation of the cranial neural crest.
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PMID:FGF2 promotes skeletogenic differentiation of cranial neural crest cells. 1149 35


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