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American Journal of Human Genetics Feb 2008Parkinson disease (PD) is a common neurodegenerative disorder caused by environmental and genetic factors. We have previously shown linkage of PD to chromosome 8p.... (Comparative Study)
Comparative Study
Parkinson disease (PD) is a common neurodegenerative disorder caused by environmental and genetic factors. We have previously shown linkage of PD to chromosome 8p. Subsequently, fibroblast growth factor 20 (FGF20) at 8p21.3-22 was identified as a risk factor in several association studies. To identify the risk-conferring polymorphism in FGF20, we performed genetic and functional analysis of single-nucleotide polymorphisms within the gene. In a sample of 729 nuclear families with 1089 affected and 1165 unaffected individuals, the strongest evidence of association came from rs12720208 in the 3' untranslated region of FGF20. We show in several functional assays that the risk allele for rs12720208 disrupts a binding site for microRNA-433, increasing translation of FGF20 in vitro and in vivo. In a cell-based system and in PD brains, this increase in translation of FGF20 is correlated with increased alpha-synuclein expression, which has previously been shown to cause PD through both overexpression and point mutations. We suggest a novel mechanism of action for PD risk in which the modulation of the susceptibility gene's translation by common variations interfere with the regulation mechanisms of microRNA. We propose this is likely to be a common mechanism of genetic modulation of individual susceptibility to complex disease.
Topics: 3' Untranslated Regions; Binding Sites; DNA Primers; Fibroblast Growth Factors; Gene Expression Regulation; Gene Frequency; Genetic Predisposition to Disease; Humans; Linkage Disequilibrium; Luciferases; MicroRNAs; Parkinson Disease; Polymorphism, Single Nucleotide; alpha-Synuclein
PubMed: 18252210
DOI: 10.1016/j.ajhg.2007.09.021 -
Molecular and Cellular Biology Sep 2009Uncontrolled fibroblast growth factor (FGF) signaling can lead to human diseases, necessitating multiple layers of self-regulatory control mechanisms to keep its...
Uncontrolled fibroblast growth factor (FGF) signaling can lead to human diseases, necessitating multiple layers of self-regulatory control mechanisms to keep its activity in check. Herein, we demonstrate that FGF9 and FGF20 ligands undergo a reversible homodimerization, occluding their key receptor binding sites. To test the role of dimerization in ligand autoinhibition, we introduced structure-based mutations into the dimer interfaces of FGF9 and FGF20. The mutations weakened the ability of the ligands to dimerize, effectively increasing the concentrations of monomeric ligands capable of binding and activating their cognate FGF receptor in vitro and in living cells. Interestingly, the monomeric ligands exhibit reduced heparin binding, resulting in their increased radii of heparan sulfate-dependent diffusion and biologic action, as evidenced by the wider dilation area of ex vivo lung cultures in response to implanted mutant FGF9-loaded beads. Hence, our data demonstrate that homodimerization autoregulates FGF9 and FGF20's receptor binding and concentration gradients in the extracellular matrix. Our study is the first to implicate ligand dimerization as an autoregulatory mechanism for growth factor bioactivity and sets the stage for engineering modified FGF9 subfamily ligands, with desired activity for use in both basic and translational research.
Topics: Amino Acid Sequence; Animals; Cells, Cultured; Crystallography, X-Ray; Diffusion; Dimerization; Extracellular Matrix; Female; Fibroblast Growth Factor 9; Fibroblast Growth Factors; Heparitin Sulfate; Humans; Ligands; Mice; Mice, Inbred C57BL; Models, Molecular; Molecular Sequence Data; Mutation; Pregnancy; Protein Multimerization; Protein Structure, Quaternary; Receptor, Fibroblast Growth Factor, Type 1; Signal Transduction
PubMed: 19564416
DOI: 10.1128/MCB.01780-08 -
American Journal of Human Genetics Jun 2004The pathogenic process responsible for the loss of dopaminergic neurons within the substantia nigra of patients with Parkinson disease (PD) is poorly understood. Current...
The pathogenic process responsible for the loss of dopaminergic neurons within the substantia nigra of patients with Parkinson disease (PD) is poorly understood. Current research supports the involvement of fibroblast growth factor (FGF20) in the survival of dopaminergic cells. FGF20 is a neurotrophic factor that is preferentially expressed within the substantia nigra of rat brain. The human homologue has been mapped to 8p21.3-8p22, which is within an area of PD linkage revealed through our published genomic screen. To test whether FGF20 influences risk of PD, we genotyped five single-nucleotide polymorphisms (SNPs) lying within the FGF20 gene, in a large family study. We analyzed our sample (644 families) through use of the pedigree disequilibrium test (PDT), the genotype PDT, the multilocus-genotype PDT, and the family-based association test to assess association between risk of PD and alleles, genotypes, multilocus genotypes, and haplotypes. We discovered a highly significant association of PD with one intronic SNP, rs1989754 (P=.0006), and two SNPs, rs1721100 (P=.02) and ss20399075 (P=.0008), located in the 3' regulatory region in our overall sample. Furthermore, we detected a haplotype (A-G-C-C-T) that is positively associated with risk of PD (P=.0003), whereas a second haplotype (A-G-G-G-C) was found to be negatively associated with risk of PD (P=.0009). Our results strongly support FGF20 as a risk factor for PD.
Topics: Base Sequence; DNA; Exons; Fibroblast Growth Factors; Genetic Predisposition to Disease; Haplotypes; Humans; Linkage Disequilibrium; Molecular Sequence Data; Parkinson Disease; Polymorphism, Single Nucleotide; Risk Factors; Sequence Homology, Nucleic Acid
PubMed: 15122513
DOI: 10.1086/421052 -
The Journal of Biological Chemistry Dec 2006The anticoagulant serpin antithrombin acquires a potent antiangiogenic activity upon undergoing conformational alterations to cleaved or latent forms. Here we show that...
Antiangiogenic antithrombin blocks the heparan sulfate-dependent binding of proangiogenic growth factors to their endothelial cell receptors: evidence for differential binding of antiangiogenic and anticoagulant forms of antithrombin to proangiogenic heparan sulfate domains.
The anticoagulant serpin antithrombin acquires a potent antiangiogenic activity upon undergoing conformational alterations to cleaved or latent forms. Here we show that antithrombin antiangiogenic activity is mediated at least in part through the ability of the conformationally altered serpin to block the proangiogenic growth factors fibroblast growth factor (FGF)-2 and vascular endothelial growth factor (VEGF) from forming signaling competent ternary complexes with their protein receptors and heparan sulfate co-receptors on endothelial cells. Cleaved and latent but not native forms of antithrombin blocked the formation of FGF-2-FGF receptor-1 ectodomain-heparin ternary complexes, and the dimerization of these complexes in solution and similarly inhibited the formation of FGF-2-heparin binary complexes and their dimerization. Only antiangiogenic forms of antithrombin likewise inhibited (125)I-FGF-2 binding to its low affinity heparan sulfate co-receptor and blocked FGF receptor-1 autophosphorylation and p42/44 MAP kinase phosphorylation in cultured human umbilical vein endothelial cells (HUVECs). Moreover, treatment of HUVECs with heparinase III to specifically eliminate the FGF-2 heparan sulfate co-receptor suppressed the ability of antiangiogenic antithrombin to inhibit growth factor-stimulated proliferation. Antiangiogenic antithrombin inhibited full-length VEGF(165) stimulation of HUVEC proliferation but did not affect the stimulation of cells by the heparin-binding domain-deleted VEGF(121). Taken together, these results demonstrate that antiangiogenic forms of antithrombin block the proangiogenic effects of FGF-2 and VEGF on endothelial cells by competing with the growth factors for binding the heparan sulfate co-receptor, which mediates growth factor-receptor interactions. Moreover, the inability of native antithrombin to bind this co-receptor implies that native and conformationally altered forms of antithrombin differentially bind proangiogenic heparan sulfate domains.
Topics: Angiogenesis Inhibitors; Anticoagulants; Antithrombins; Cell Proliferation; Cells, Cultured; Endothelial Cells; Fibroblast Growth Factors; Heparin; Heparin Lyase; Heparitin Sulfate; Humans; Protein Binding; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Vascular Endothelial Growth Factor A
PubMed: 17040907
DOI: 10.1074/jbc.M604905200 -
BMC Genomics Feb 2013The theoretical basis of genome-wide association studies (GWAS) is statistical inference of linkage disequilibrium (LD) between any polymorphic marker and a putative...
BACKGROUND
The theoretical basis of genome-wide association studies (GWAS) is statistical inference of linkage disequilibrium (LD) between any polymorphic marker and a putative disease locus. Most methods widely implemented for such analyses are vulnerable to several key demographic factors and deliver a poor statistical power for detecting genuine associations and also a high false positive rate. Here, we present a likelihood-based statistical approach that accounts properly for non-random nature of case-control samples in regard of genotypic distribution at the loci in populations under study and confers flexibility to test for genetic association in presence of different confounding factors such as population structure, non-randomness of samples etc.
RESULTS
We implemented this novel method together with several popular methods in the literature of GWAS, to re-analyze recently published Parkinson's disease (PD) case-control samples. The real data analysis and computer simulation show that the new method confers not only significantly improved statistical power for detecting the associations but also robustness to the difficulties stemmed from non-randomly sampling and genetic structures when compared to its rivals. In particular, the new method detected 44 significant SNPs within 25 chromosomal regions of size < 1 Mb but only 6 SNPs in two of these regions were previously detected by the trend test based methods. It discovered two SNPs located 1.18 Mb and 0.18 Mb from the PD candidates, FGF20 and PARK8, without invoking false positive risk.
CONCLUSIONS
We developed a novel likelihood-based method which provides adequate estimation of LD and other population model parameters by using case and control samples, the ease in integration of these samples from multiple genetically divergent populations and thus confers statistically robust and powerful analyses of GWAS. On basis of simulation studies and analysis of real datasets, we demonstrated significant improvement of the new method over the non-parametric trend test, which is the most popularly implemented in the literature of GWAS.
Topics: Algorithms; Case-Control Studies; Cohort Studies; Computer Simulation; Databases, Factual; Fibroblast Growth Factors; Genome-Wide Association Study; Genotype; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Likelihood Functions; Linkage Disequilibrium; Models, Statistical; Parkinson Disease; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases
PubMed: 23394771
DOI: 10.1186/1471-2164-14-88 -
Translational Psychiatry Feb 2015Pharmacogenetics may allow for a personalized treatment, but a combination with clinical variables may further enhance prediction. In particular, in the present paper,... (Randomized Controlled Trial)
Randomized Controlled Trial
Genetic variants in combination with early partial improvement as a clinical utility predictor of treatment outcome in major depressive disorder: the result of two pooled RCTs.
Pharmacogenetics may allow for a personalized treatment, but a combination with clinical variables may further enhance prediction. In particular, in the present paper, we investigated early partial improvement (EPI) defined as 20% or more improvement by rating scales 2 weeks after treatment, in combination with selected gene variants as a predictor of treatment outcome in patients with major depressive disorder. Two randomized controlled trials with 168 Japanese depressed patients were used. A stepwise multiple linear regression model with HAM-D score change at week 6 as the dependent variable and genotypes, EPI, baseline HAM-D score, age and sex as independent variables was performed in paroxetine, fluvoxamine and milnacipran, respectively, to estimate the prediction of HAM-D change at week 6. In the paroxetine sample, only EPI (P<0.001) was significantly associated with HAM-D change (n=81, R(2)=0.25, P<0.001). In the fluvoxamine sample, 5-HTTLPR La/Lg, S (P=0.029), FGF2 rs1449683C/T (P=0.013) and EPI (P=0.003) were associated with HAM-D change (n=42, R(2)=0.43, P<0.001). In the milnacipran sample, HTR-1A-1019C/G (P=0.001), ADRA2A-1297C/G (P=0.028) and EPI (P<0.001) were associated with outcome (n=45, R(2)=0.71, P<0.001). EPI in combination with genetic variants could be a useful predictor of treatment outcome and could strengthen the practical use of pharmacogenetic data in clinical practice.
Topics: Age Factors; Antidepressive Agents; Antidepressive Agents, Second-Generation; Cyclopropanes; Depressive Disorder, Major; Female; Fibroblast Growth Factors; Fluvoxamine; Humans; Japan; Male; Middle Aged; Milnacipran; Paroxetine; Psychiatric Status Rating Scales; Receptor, Serotonin, 5-HT1A; Receptors, Adrenergic, alpha-2; Serotonin Plasma Membrane Transport Proteins; Sex Factors; Treatment Outcome
PubMed: 25710119
DOI: 10.1038/tp.2015.6 -
Scientific Reports Jun 2019Endogenous fibroblast growth factor 20 (FGF20) supports maintenance of dopaminergic neurones within the nigrostriatal pathway. Moreover, direct intracerebral infusion of...
Endogenous fibroblast growth factor 20 (FGF20) supports maintenance of dopaminergic neurones within the nigrostriatal pathway. Moreover, direct intracerebral infusion of FGF20 protects against nigrostriatal tract loss in the 6-hydroxydopamine lesion rat model of Parkinson's disease. Increasing endogenous FGF20 production might provide a less-invasive, more translational way of providing such protection. Accordingly, we adopted a targeted repositioning approach to screen for candidate FDA-approved drugs with potential to enhance endogenous FGF20 production in brain. In silico interrogation of the Broad Institute's Connectivity Map database (CMap), revealed 50 candidate drugs predicted to increase FGF20 transcription, 16 of which had profiles favourable for use in Parkinson's disease. Of these, 11 drugs were found to significantly elevate FGF20 protein production in MCF-7 cells, between two- and four-fold. Four drugs were selected for examination in vivo. Following oral dosing in rats for 7 days, salbutamol and triflusal, but not dimethadione or trazodone, significantly elevated FGF20 levels in the nigrostriatal tract. Preliminary examination in the unilateral 6-hydroxydopamine-lesioned rat revealed a modest but significant protection against nigral cell loss with both drugs. Our data demonstrate the power of targeted repositioning as a method to identify existing drugs that may combat disease progression in Parkinson's by boosting FGF20 levels.
Topics: Albuterol; Animals; Brain; Computer Simulation; Corpus Striatum; Dimethadione; Dopaminergic Neurons; Drug Repositioning; Female; Fibroblast Growth Factors; Humans; MCF-7 Cells; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Rats; Rats, Sprague-Dawley; Salicylates; Substantia Nigra; Trazodone; Treatment Outcome
PubMed: 31171821
DOI: 10.1038/s41598-019-44803-1 -
Medecine Sciences : M/S Mar 2013
Topics: Animals; Cell Differentiation; Female; Fibroblast Growth Factor 9; Fibroblast Growth Factors; Humans; Kidney; Pregnancy; Renal Insufficiency; Stem Cells
PubMed: 23544377
DOI: 10.1051/medsci/2013293009 -
BMC Neurology Jun 2005Fibroblast growth factor 20 (FGF20) is a neurotrophic factor preferentially expressed in the substantia nigra of rat brain and could be involved in dopaminergic neurons... (Comparative Study)
Comparative Study
BACKGROUND
Fibroblast growth factor 20 (FGF20) is a neurotrophic factor preferentially expressed in the substantia nigra of rat brain and could be involved in dopaminergic neurons survival. Recently, a strong genetic association has been found between FGF20 gene and the risk of suffering from Parkinson's disease (PD). Our aim was to replicate this association in two independent populations.
METHODS
Allelic, genotypic, and haplotype frequencies of four biallelic polymorphisms were assessed in 151 sporadic PD cases and 186 controls from Greece, and 144 sporadic PD patients and 135 controls from Finland.
RESULTS
No association was found in any of the populations studied.
CONCLUSION
Taken together, these findings suggest that common genetic variants in FGF20 are not a risk factor for PD in, at least, some European populations.
Topics: Adult; Aged; Aged, 80 and over; Alleles; Case-Control Studies; Fibroblast Growth Factors; Finland; Gene Frequency; Genotype; Greece; Humans; Linkage Disequilibrium; Middle Aged; Parkinson Disease; Polymorphism, Genetic; Prospective Studies
PubMed: 15967032
DOI: 10.1186/1471-2377-5-11 -
The Journal of Neuroscience : the... Sep 2006The specific expression of fibroblast growth factor 20 (FGF-20) in the adult substantia nigra and the association between FGF-20 mutations and Parkinson's disease... (Comparative Study)
Comparative Study
The specific expression of fibroblast growth factor 20 (FGF-20) in the adult substantia nigra and the association between FGF-20 mutations and Parkinson's disease provoked exploration of the function of this growth factor. We show by gain- and loss-of-function in vitro experiments that FGF-20 promotes survival and stimulates dopamine (DA) release in a calbindin-negative subset of cells that are preferentially lost in Parkinson's disease. FGF-20 selectively activates tyrosine hydroxylase in calbindin-negative neurons. In the adult substantia nigra, calbindin-negative neurons specifically express high levels of FGFR1 (FGF receptor 1). These data show that FGF signals to elevate DA levels and protect the specific midbrain neuron type at most risk in Parkinson's patients.
Topics: Animals; Cell Survival; Cells, Cultured; Dopamine; Fibroblast Growth Factors; Humans; Mesencephalon; Parkinson Disease; Rats; Risk; Substantia Nigra
PubMed: 16988046
DOI: 10.1523/JNEUROSCI.2745-06.2006