Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Dominantly acting mutations of the fibroblast growth factor (FGF) receptor 2 (FGFR2) gene have been implicated in various craniosynostosis syndromes. Apert syndrome, characterized in addition by syndactyly of the limbs, involves specific mutations at two adjacent residues, Ser252Trp and Pro253Arg, predicted to lie in the linker region between IgII and IgIII of the FGFR2 ligand-binding domain. We have analysed the interaction of FGF ligands with wild-type and Apert-type mutant FGFR2 ectodomains in solution. Wild-type and Apert-type receptors form a complex with FGF ligands with a stoichiometry of 2:2 (ligand:receptor). The kinetics and specificity of ligand binding to wild-type and Apert mutant receptors have been analysed using surface plasmon resonance techniques. This reveals that Apert mutations, compared with wild-type, exhibit a selective decrease in the dissociation kinetics of FGF2, but not of other FGF ligands examined. In contrast, the substitution Ser252Leu in FGFR2, previously observed in several asymptomatic individuals, exhibited wild-type kinetics. These findings indicate that Apert syndrome arises as a result of increased affinity of mutant receptors for specific FGF ligands which leads to activation of signalling under conditions where availability of ligand is limiting.
Hum Mol Genet 1998 Sep
PMID:Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand. 970 Feb 3

H-TWIST belongs to the family of basic helix-loop-helix (bHLH) transcription factors known to exert their activity through dimer formation. We have demonstrated recently that mutations in H-TWIST account for Saethre-Chotzen syndrome (SCS), an autosomal dominant craniosynostosis syndrome characterized by premature fusion of coronal sutures and limb abnormalities of variable severity. Although insertions, deletions, nonsense and missense mutations have been identified, no genotype-phenotype correlation could be found, suggesting that the gene alterations lead to a loss of protein function irrespective of the mutation. To assess this hypothesis, we studied stability, dimerization capacities and subcellular distribution of three types of TWIST mutant. Here, we show that: (i) nonsense mutations resulted in truncated protein instability; (ii) missense mutations involving the helical domains led to a complete loss of H-TWIST heterodimerization with the E12 bHLH protein in the two-hybrid system and dramatically altered the ability of the TWIST protein to localize in the nucleus of COS-transfected cells; and (iii) in-frame insertion or missense mutations within the loop significantly altered dimer formation but not the nuclear location of the protein. We conclude that at least two distinct mechanisms account for loss of TWIST protein function in SCS patients, namely protein degradation and subcellular mislocalization.
Hum Mol Genet 2000 Mar 22
PMID:Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location. 1074 89

Foramina parietalia permagna (FPP) is an autosomal dominant condition characterized by cranial defects of the parietal bones. It can be present as an isolated feature, but it is also one of the characteristics of a contiguous gene syndrome associated with deletions on chromosome 11p11-p12. One of the proteins known to be involved in skull development is the MSX2 homeobox protein. Previously, MSX2 has been shown to be mutated in patients suffering from Boston type craniosynostosis. We have now analyzed the MSX2 gene in five families affected with FPP. An intragenic microsatellite marker did not reveal any recombination and a cumulated LOD score of +3.2 at theta = 0 was obtained. Sequence analysis further showed that in four out of five families an MSX2 mutation was responsible for the skull defect. Moreover, it appears that FPP is caused by haplo-insufficiency of the MSX2 gene. This implies that Boston type craniosynostosis and FPP are allelic variants of the same gene, with FPP caused by loss of MSX2 function and craniosynostosis Boston type due to gain of MSX2 function.
Hum Mol Genet 2000 May 01
PMID:Identification of mutations in the MSX2 homeobox gene in families affected with foramina parietalia permagna. 1076 51

Pfeiffer syndrome is a classic form of craniosynostosis that is caused by a proline-->arginine substitution at amino acid 252 (Pro252Arg) in fibroblast growth factor receptor 1 (FGFR1). Here we show that mice carrying a Pro250Arg mutation in Fgfr1, which is orthologous to the Pfeiffer syndrome mutation in humans, exhibit anterio-posteriorly shortened, laterally widened and vertically heightened neurocraniums. Analysis of the posterior and anterior frontal, sagittal and coronal sutures of early post-natal mutant mice revealed premature fusion. The sutures of mutant mice had accelerated osteoblast proliferation and increased expression of genes related to osteoblast differentiation, suggesting that bone formation at the sutures is locally increased in Pfeiffer syndrome. Of note, dramatically increased expression of core-binding transcription factor alpha subunit type 1 (Cbfa1) accompanied premature fusion, suggesting that Cbfa1 may be a downstream target of Fgf/Fgfr1 signals. This was confirmed in vitro, where we demonstrate that transfection with wild-type or mutant Fgfr1 induces Cbfa1 expression. The induced expression was also observed using Fgf ligands (Fgf2 and Fgf8). These studies provide direct genetic evidence that the Pro252Arg mutation in FGFR1 causes human Pfeiffer syndrome and uncovers a molecular mechanism in which Fgf/Fgfr1 signals regulate intramembraneous bone formation by modulating Cbfa1 expression.
Hum Mol Genet 2000 Aug 12
PMID:A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures. 1094 29

Crouzon syndrome is a dominantly inherited craniosynostosis syndrome which is caused by mutations in the fibroblast growth factor receptor 2 gene (FGFR2). However, a specific point mutation in the FGFR3 gene has also been shown to result in Crouzon syndrome associated with acanthosis nigricans. We report here the first method for preimplantation genetic diagnosis (PGD) of Crouzon syndrome based on multiplex PCR amplification followed by the direct detection of the causative mutation by single-stranded conformational polymorphism (SSCP) analysis. A highly polymorphic short tandem repeat (STR) locus was simultaneously analysed as a control against some forms of contamination. The mutation, carried by the female partner, was a de-novo substitution at codon 338 of the FGFR2 gene. The couple were found to be informative at the D21S11 STR locus. Two clinical PGD cycles were performed, resulting in the biopsy of 36 blastomeres, 25 of which showed amplification at the FGFR2 locus. All of the cells showed expected genotypes at the D21S11 locus with only one incidence of allele drop-out. A total of five embryos were transferred, two in the first cycle and three in the second, resulting in a singleton pregnancy.
Mol Hum Reprod 2002 Mar
PMID:Pregnancy following preimplantation genetic diagnosis for Crouzon syndrome. 1187 Feb 39

Thyroid hormone (T3) regulates bone turnover and mineralization in adults and is essential for skeletal development during childhood. Hyperthyroidism is an established risk factor for osteoporosis. Nevertheless, T3 actions in bone remain poorly understood. Patients with resistance to thyroid hormone, due to mutations of the T3-receptor beta (TRbeta) gene, display variable phenotypic abnormalities, particularly in the skeleton. To investigate the actions of T3 during bone development, we characterized the skeleton in TRbetaPV mutant mice. TRbetaPV mice harbor a targeted resistance to thyroid hormone mutation in TRbeta and recapitulate the human condition. A severe phenotype, which includes shortened body length, was evident in homozygous TRbetaPV/PV animals. Accelerated growth in utero was associated with advanced endochondral and intramembranous ossification. Advanced bone formation resulted in postnatal growth retardation, premature quiescence of the growth plates, and shortened bone length, together with increased bone mineralization and craniosynostosis. In situ hybridization demonstrated increased expression of fibroblast growth factor receptor-1, a T3-regulated gene in bone, in TRbetaPV/PV perichondrium, growth plate chondrocytes, and osteoblasts. Thus, the skeleton in TRbetaPV/PV mice is thyrotoxic and displays phenotypic features typical of juvenile hyperthyroidism.
Mol Endocrinol 2003 Jul
PMID:A thyrotoxic skeletal phenotype of advanced bone formation in mice with resistance to thyroid hormone. 1267 5

Craniosynostosis results in cranial deformities and increased intracranial pressure, which pose extensive and recurrent surgical management problems. Developmental studies in rodents have shown that low levels of transforming growth factor-beta 3 (Tgf-beta 3) are associated with normal fusion of the interfrontal (IF) suture, and that Tgf-beta 3 prevents IF suture fusion in a dose-dependent fashion. The present study was designed to test the hypothesis that Tgf-beta 3 can also prevent or "rescue" fusing sutures in a rabbit model with familial craniosynostosis. One hundred coronal sutures from 50 rabbits with delayed-onset, coronal suture synostosis were examined in the present study. The rabbits were divided into five groups of 10 rabbits each: 1) sham controls, 2) bovine serum albumin (BSA, 500 ng) low-dose protein controls, 3) low-dose Tgf-beta 3 (500 ng), 4) high-dose BSA (1,000 ng) controls, and 5) high-dose Tgf-beta 3 (1,000 ng). At 10 days of age, radiopaque amalgam markers were implanted in all of the rabbits on either side of the coronal suture to monitor sutural growth. At 25 days of age, the BSA or Tgf-beta 3 was combined with a slow-absorbing collagen vehicle and injected subperiosteally above the coronal suture. Radiographic results revealed that high-dose Tgf-beta 3 rabbits had significantly greater (P < 0.05) coronal suture marker separation than the other groups. Histomorphometric analysis revealed that high-dose Tgf-beta 3 rabbits also had patent coronal sutures and significantly (P < 0.01) greater sutural widths and areas than the other groups. The results suggest that there is a dose-dependent effect of TGF-beta 3 on suture morphology and area in these rabbits, and that the manipulation of such growth factors may have clinical applications in the treatment of craniosynostosis.
Anat Rec A Discov Mol Cell Evol Biol 2003 Oct
PMID:Rescue of coronal suture fusion using transforming growth factor-beta 3 (Tgf-beta 3) in rabbits with delayed-onset craniosynostosis. 1297 20

p190RhoGEF is a large multi-functional protein with guanine nucleotide exchange (GEF) activity. The C-terminal region of p190RhoGEF is a highly interactive domain that binds multiple factors, including proteins with anti-apoptotic activities. We now report that transfection of EGFP-tagged p190RhoGEF protects Neuro 2a cells from stress-induced apoptosis and that anti-apoptotic activity is localized to cytoplasmic retention sequences (CRS-1 and CRS-2) in the C-terminal region of p190RhoGEF. Cytoplasmic retention is conferred to an EGFP fluorescent marker when fused to either CRS-1 or CRS-2. Both cytoplasmic retention and anti-apoptotic activity are lost by deleting CRS-1 and CRS-2 in the p190RhoGEF sequence and can be recovered by restoring either CRS-1 or CRS-2 to the EGFP-tagged sequence. Since the CRS-1 and CRS-2 contain the JIP-1 and 14-3-3 binding sites, we propose that anti-apoptotic activity may be conferred by the binding of p190RhoGEF to JIP-1 or 14-3-3, possibly by altering their interactive properties or nucleocytoplasmic movements. Taken together, our findings support a model whereby multiple interactions of p190RhoGEF confer homeostatic properties to differentiated neurons and may link neuronal homeostasis to the regulation of NF-L expression.
Brain Res Mol Brain Res 2003 Sep 10
PMID:Cytoplasmic retention sites in p190RhoGEF confer anti-apoptotic activity to an EGFP-tagged protein. 1449 78

Identical proline-->arginine gain-of-function mutations in fibroblast growth factor receptor (FGFR) 1 (Pro252Arg), FGFR2 (Pro253Arg) and FGFR3 (Pro250Arg), result in type I Pfeiffer, Apert and Muenke craniosynostosis syndromes, respectively. Here, we characterize the effects of proline-->arginine mutations in FGFR1c and FGFR3c on ligand binding using surface plasmon resonance and X-ray crystallography. Both Pro252Arg FGFR1c and Pro250Arg FGFR3c exhibit an enhancement in ligand binding in comparison to their respective wild-type receptors. Interestingly, binding of both mutant receptors to FGF9 was notably enhanced and implicates FGF9 as a potential pathophysiological ligand for mutant FGFRs in mediating craniosynostosis. The crystal structure, of Pro252Arg FGFR1c in complex with FGF2, demonstrates that the enhanced ligand binding is due to an additional set of receptor-ligand hydrogen bonds, similar to those gain-of-function interactions that occur in the Apert syndrome Pro253Arg FGFR2c-FGF2 crystal structure. However, unlike the Apert syndrome Pro253Arg FGFR2c mutant, neither the Pfeiffer syndrome Pro250Arg FGFR1c mutant nor the Muenke syndrome Pro250Arg FGFR3c mutant bound appreciably to FGF7 or FGF10. This observation provides a potential explanation for why the limb phenotypes, observed in type I Pfeiffer and Muenke syndromes, are less severe than the limb abnormalities observed in Apert syndrome. Hence, although analogous proline-->arginine mutations in FGFR1-3 act through a common structural mechanism to result in gain-of-function, differences in the primary sequence among FGFRs result in varying effects on ligand binding specificity.
Hum Mol Genet 2004 Jan 01
PMID:Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity. 1461 73

Premature fusion of cranial sutures underlies the clinical condition of 'craniosynostosis', a common human disorder that occurs in both nonsyndromic and syndromic forms. The subgroup of syndromic craniosynostoses usually associates limb abnormalities and facial dysmorphism to skull distortion. Over the past decade, some of the genes causing these phenotypes have been identified. Among these, the gene encoding FGFR2, one of four members of the fibroblast growth factor receptor(FGFR) family, has been shown to account for several severe conditions including Apert, Pfeiffer, Crouzon, Beare-Stevenson and Jackson-Weiss syndromes. Two other FGFRs, FGFR1 and FGFR3, also account for craniosynostoses of variable severity [Pfeiffer, Crouzon with acanthosis nigricans (a pre-malignant skin disorder), and Muenke syndromes]. By contrast,Saethre-Chotzen syndrome and craniosynostosis (Boston-type) arise from mutations in the Twist and muscle segment homeobox 2 (MSX2) transcription factors, respectively. Whereas most FGFR mutations are likely to cause ligand independent activation of the receptor, leading to an upregulation of signaling pathways, mutations in the basic helix-loop-helix (bHLH) transcription factor Twist appear to induce loss of protein function. This review will summarise and discuss some of the cellular and molecular mechanisms involved in normal and abnormal craniofacial development, focusing on the possible interactions between the different factors controlling membranous ossification.
Expert Rev Mol Med 2003 Jan 29
PMID:Molecular and cellular bases of syndromic craniosynostoses. 1498 7


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