Fyn Gene Research Articles

The association of single nucleotide polymorphism of the Fyn gene with sporadic Alzheimer's disease in the Chinese Han population

Recent studies suggested genetic factors contribute to the pathogenesis of sporadic Alzheimer's disease (sAD). Fibroblast Yes related novel (Fyn), a tau kinase, has been reported to be associated with aberrant phosphorylated tau and neurofibrillary tangles formation. Fyn gene may be a potential candidate gene for AD. To investigate the association of the polymorphisms in Fyn gene with the susceptibility to sAD, we conducted a case–control study in a Chinese Han cohort including 200 sAD patients and 243 control participants. Four single nucleotide polymorphisms (SNPs) (rs111787668, rs1057979, rs6916861 and rs12910) within the promoter region of Fyn gene and one (rs7768046) in intron were selected and genotyped with a polymerase chain reaction–ligase detection reaction (PCR–LDR) method. Logistic regression under four genetic models was used to analyze the association between target SNPs and the risk of sAD. After adjusting for age, sex and APOE ɛ4 status, no association was revealed between these SNPs or the haplotypes containing four SNPs and the risk of sAD (P>0.05). The SNPs in the selected regions of the Fyn gene are unlikely to confer the susceptibility of sAD in the Chinese Han population. Further studies with a larger sample size and different ethnic populations are needed to reveal the role of Fyn gene in the pathogenesis of sAD.

Mouse Fyn induces pseudopodium formation in Chinese hamster ovary cells

Molecular mechanisms underlying the effects of Fyn on cell morphology, pseudopodium movement, and cell migration were investigated. The Fyn gene was subcloned into pEGFP-N1 to produce pEGFP-N1-Fyn. Chinese hamster ovary (CHO) cells were transfected with pEGFP-N1-Fyn. The expression of Fyn mRNA and proteins was monitored by reverse transcription-PCR and Western blotting. Additionally, transfected cells were stained with 4',6-diamidino-2-phenylindole and a series of time-lapse images was taken. Sequences of the recombinant plasmids pMD18-T-Fyn and pEGFP-N1-Fyn were confirmed by sequence identification using National Center for Biotechnology Information in USA, and Fyn expression was detected by RT-PCR and Western blotting. The morphology of CHO cells transfected with the recombinant vector was significantly altered. Fyn expression induced filopodia and lamellipodia formation. Based on these results, we concluded that overexpression of mouse Fyn induces the formation of filopodia and lamellipodia in CHO cells, and promotes cell movement.

Genetic variation of FYN contributes to the molecular mechanisms of coping styles in healthy Chinese-Han participants

Genetic factors can influence specific human coping styles. Polymorphisms in the Src family tyrosine kinase FYN gene have been associated with several personality traits, but no studies have examined the possible relationship between FYN alleles and coping styles. To this end, we examined the association between three single nucleotide polymorphisms of FYN (rs706895, rs3730353, and rs6916861) and coping styles as measured by the Simplified Coping Style Questionnaire in 488 healthy Chinese-Han individuals. In the total sample population, there were no significant differences in the scores for active coping and passive coping among the genotypes of these three polymorphisms. In sex-specific analyses, however, both rs3730353 and rs6916861 polymorphisms showed a significant relationship with passive coping scores in female participants (rs3730353: χ(2)=8.08, P=0.018; rs6916861: χ(2)=7.78, P=0.020). Our results provided suggestive evidence that the FYN gene contributes toward the variance in human coping styles.

Association study of the Fyn gene with schizophrenia in the Chinese-Han population

Department of Psychiatry, The First Affiliated Hospital, Department of Scientific Research and Subject Construction, Shengjing Hospital, China Medical University and Shenyang Mental Health Center, Shenyang, China Correspondence to Professor Gang Zhu, MD, PhD, Department of Psychiatry, The First Affiliated Hospital, China Medical University, Shenyang 110001, China Tel:/fax: + 86-24-83282184; e-mail: gzhu@mail.cmu.edu.cn

Association Study of FYN Gene Polymorphism and Methamphetamine Use Disorder

Fyn kinase belongs to the Src family of tyrosine kinases and phosphorylates NMDA receptor subunits. The Fyn kinase gene, FYN, has been considered to be involved in the pathophysiologies of neuropsychiatric diseases. We examined three polymorphisms, rs706895, rs3730353, and rs6916861, of the FYN gene in 250 patients with methamphetamine use disorder and 275 controls. There were no significant differences between the patients and controls in genotype or allele distribution. In haplotype association analyses, the C-T haplotype at rs3730353-rs6916861 showed a significant association with methamphetamine use disorder. We also analyzed the clinical phenotypes of methamphetamine use disorder. Rs3730353 and rs6916861 showed a significant association with age at first consumption in genotype and allele distributions, and multiple- substance abuse status in the genotype distribution. The present study suggests that genetic variation of the FYN gene may be related to the severity of methamphetamine use disorder in a Japanese population.

Fyn gene polymorphisms contribute to both trait and state anxieties in healthy Chinese-Han individuals

Li, Jingying*; Zhou, Hongxu*; Ma, Huan; Wei, Yuan; Huang, Yinglin; Wu, Lijuan; Jin, Qiu; Zhao, Xiaofeng; Zhu, Gang Author Information

Mouse Skeletal Muscle Fiber-Type-Specific Macroautophagy and Muscle Wasting Are Regulated by a Fyn/STAT3/Vps34 Signaling Pathway

Skeletal muscle atrophy induced by aging (sarcopenia), inactivity, and prolonged fasting states (starvation) is predominantly restricted to glycolytic type II muscle fibers and typical spares oxidative type I fibers. However, the mechanisms accounting for muscle fiber-type specificity of atrophy have remained enigmatic. In the current study, although the Fyn tyrosine kinase activated the mTORC1 signaling complex, it also induced marked atrophy of glycolytic fibers with relatively less effect on oxidative muscle fibers. This was due to inhibition of macroautophagy via an mTORC1-independent but STAT3-dependent reduction in Vps34 protein levels and decreased Vps34/p150/Beclin1/Atg14 complex 1. Physiologically, in the fed state endogenous Fyn kinase activity was increased in glycolytic but not oxidative skeletal muscle. In parallel, Y705-STAT3 phosphorylation increased with decreased Vps34 protein levels. Moreover, fed/starved regulation of Y705-STAT3 phosphorylation and Vps34 protein levels was prevented in skeletal muscle of Fyn null mice. These data demonstrate a Fyn/STAT3/Vps34 pathway that is responsible for fiber-type-specific regulation of macroautophagy and skeletal muscle atrophy.

Fyn Polymorphisms are Associated with Distinct Personality Traits in Healthy Chinese-Han Subjects

The Src family tyrosine kinase Fyn regulates a myriad of neurophysiological processes, including learning and memory. To date, the role of Fyn in the neurological mechanisms that determine personality traits has not been addressed. To this end, we determined the association between the rs706895C/T polymorphism of the Fyn gene (FYN) and personality traits measured by the Tridimensional Personality Questionnaire in 502 healthy Chinese-Han subjects. There were no significant differences in the total scores for novelty seeking (χ² = 5.12, P = 0.077), harm avoidance (HA; χ² = 2.63, P = 0.269), or reward dependence (RD; χ² = 3.94, P = 0.139) among the rs706895C/T genotypes. In sub-item analyses, however, both fear of uncertainty (HA2; χ² = 7.84, P = 0.020) and sentimentality (RD1; χ² = 8.27; P = 0.016) scores were significantly different among rs706895C/T genotypes. Our results suggest that FYN alleles can contribute to the variance in human personality traits.

Comparison of mRNA expression levels of selected genes in the brain stem of cattle naturally infected with classical and atypical BSE

Since 2004 cases of atypical bovine spongiform encephalopathy (BSE) in older cattle are recorded on the basis of aberrant glycoprofiles of prion protein resistant to proteolysis (PrPres). The nature of those types of PrPres is still not fully understood but the epidemiological data indicate that their occurrence is rare. Hitherto, most BSE cases were studied on the basis of the features of pathological form of prion protein (PrPSc) or lesions observed in the gray matter of the brain. Here we propose the gene expression profiling as a method to characterize and distinguish BSE types. Thus, the aim of the study was to compare the activity of some genes which are known to play a role in the pathogenesis of transmissible spongiform encephalopathies (TSEs). Significant differences in the expression level of the selected genes in the brain stem were observed for 7 out of 11 genes tested when the results for BSE affected and healthy control animals were compared. Significant up-regulation of caspase 3, Bax and 14-3-3 protein encoding genes was apparent in the obex of all BSE affected cattle regardless of the prion type. Significant and unique to BSE H-type up-regulation was detected in prion and SOD1 genes, while BSE C-type was characterized by higher Bcl-2 and Fyn gene expression levels in respect to other BSE types and control animals. Different gene expression profiles of bovine brains infected with classical and atypical BSE indicate possible different pathogenesis or origin of the disease.

P.1.a.025 Association study of rs6916861 polymorphism of the FYN gene in bipolar disorder and it subtypes

P.1.a.025 Association study of rs6916861 polymorphism of the FYN gene in bipolar disorder and it subtypes

Decreased expression of Fyn protein and disbalanced alternative splicing patterns in platelets from patients with schizophrenia

Fyn, a Src-family kinase, is highly expressed in brain tissue and blood cells. In the mouse brain, Fyn participates in brain development, synaptic transmission through the phosphorylation of N-methyl- d-aspartate (NMDA) receptor subunits, and the regulation of emotional behavior. Recently, we found that Fyn is required for the signal transduction in striatal neurons that is initiated by haloperidol, an antipsychotic drug. To determine whether Fyn abnormalities are present in patients with schizophrenia, we analyzed Fyn expression in platelet samples from 110 patients with schizophrenia, 75 of the patients' first-degree relatives, and 130 control subjects. A Western blot analysis revealed significantly lower levels of Fyn protein among the patients with schizophrenia and their relatives, compared with the level in the control group. At the mRNA level, the splicing patterns of fyn were altered in the patients and their relatives; specifically, the ratio of fynΔ7, in which exon 7 is absent, was elevated. An expression study in HEK293T cells revealed that FynΔ7 had a dominant-negative effect on the phosphorylation of Fyn's substrate. These results suggest novel deficits in Fyn function, manifested as the downregulation of Fyn protein or the altered transcription of the fyn gene, in patients with schizophrenia.

FYN Kinase Gene: Another Glutamatergic Gene Associated with Bipolar Disorder?

Several genes of the glutamatergic system have been implicated in both schizophrenia and bipolar disorder. The Src family tyrosine kinase FYN plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate. Although no association between FYN gene polymorphisms and schizophrenia has been demonstrated, in our previous paper we found an association between FYN polymorphisms and cognitive test performance in schizophrenic patients. The aim of this study was to find a possible association of three polymorphisms of the FYN gene with bipolar disorder. We analyzed 425 bipolar patients and 518 control subjects. Genotypes of three analyzed polymorphisms, i.e. rs706895 (–93A/G in the 5′-flanking region), rs6916861 (Ex12+894T/G in the 3′-UTR) and rs3730353 (IVS10+37T/C in intron 10) were established by PCR-RFLP. A significant association was found between rs6916861 T/G and rs3730353 T/C polymorphisms of the FYN gene and bipolar disorder. These results were also significant in the subgroups of bipolar I and early-onset (<18 years) bipolar disorder patients. No association with –93 A/G polymorphism was found. Haplotype analysis revealed that rs6916861 T/G and rs3730353 T/C polymorphisms are in linkage disequilibrium (r² = 0.86, D′ = 0.93 with 95% CI = 0.9–0.97). The results suggest that the glutamatergic FYN gene may be associated with bipolar disorder, particularly with type I illness and early age of onset.

The association study of three FYN polymorphisms with prophylactic lithium response in bipolar patients

FYN belongs to the protein kinase family that phosphorylates NMDA receptor subunits, participating in the regulation of ion transmission and BDNF/TrkB signal transduction pathway. Lithium inhibits glutamatergic transmission via NMDA receptors, exerting neuroprotective effect against excitotoxicity. The aim of this study was to find possible association of three polymorphisms of FYN gene with prophylactic lithium response in the group of bipolar patients. We analyzed 101 bipolar patients treated with lithium carbonate for 5-27 years (mean 15 years). Twenty-four patients were identified as excellent lithium responders (ER), 51 patients as partial responders (PRs), and 26 patients were non-responders. Genotypes of the three analyzed polymorphisms were established by PCR-RFLP. Statistical analysis was done with Statistica. No significant differences in genotype distribution and allele frequencies were observed between T/G and A/G FYN polymorphisms and lithium response. We observed a trend toward association of TT genotype and T allele of T/C polymorphism with worse lithium response. The results of the study demonstrated only marginal association between FYN polymorphisms and prophylactic lithium response in bipolar patients. The results are discussed in light of our previous studies on FYN gene in bipolar illness and BDNF gene in lithium response.

Genetic association between −93A/G polymorphism in the Fyn kinase gene and alcohol dependence in Spanish men

Background Fyn tyrosine kinase is a member of the Scr family that phosphorylates the NR2A and NR2B subunits of the NMDA receptors reducing the inhibitory effects of ethanol and therefore may regulate the individual sensitivity to ethanol. Objectives To investigate whether there is any relationship between the polymorphism at position −93 of the Fyn kinase gene and the susceptibility to develop alcoholism. Methods We studied the distribution of genotypes and alleles of the polymorphism −93A/G (137346 T/C) in the 5′ UTR region of the fyn gene in 207 male heavy drinkers (119 with alcohol dependence and 88 with alcohol abuse) and 100 control subjects from Castilla y León (Spain). Results The frequency of G allele carriers was higher in alcohol dependents than in alcohol abusers (47.9% vs 30.6%; p = 0.015; OR = 2.077; 95% CI 1.165–3.704). Conclusion Our results show that the −93G allele of Fyn kinase gene is associated with higher risk to develop alcohol dependence in Spanish men.

Glutamatergic and dopaminergic system genes polymorphism in prefrontal tests performance in schizophrenia, bipolar disorders and in healthy subjects

Prefrontal functions impairment in schizophrenia and bipolar disorder are are markers of vulnerability to the diseases. Our previous data showed association between Wisconsin Card Sorting Test (WCST) performance in schizophrenia with the polymorphism of dopaminergic genes)COMT, DRD 1) and with polymorphism of Brain-derived neurotrophic factor (BDNF) in bipolar disorders. The Src-family tyrosine kinase Fyn plays important role in the interaction between BDNF and glutamatergic receptor NMDA in prefrontal cortex. The possible association between the polymorphisms of BDNF and Fyn genes and performance on WCST and N-back tests in healthy subjects were assessed in 200 healthy persons, genotyped for the two polymorphism of BDNF gene (C/T, Val66Met) and three polymorphisms of the Fyn gene (-93 A/G, IVS10+37T/C, Ex12+894T/G). In the whole group, the T/T genotype of C-270T BDNF polymorphism was associated with higher percentage of conceptual responses on WCST. Male subjects with C/T genotype obtained better results on percentage of correct reactions in N-back test. No significant differences between any of Fyn gene polymorphisms and WCST performance were found. Better results on percentage of correct reactions in N-back test were obtained by subjects with G/G genotype of 93A/G polymorphism and with G/G genotype of FYN T/G polymorphism. Female subjects having T/T polymorphism of T/C polymorphism performed better as to percentage of correct reactions in N-back test. The results obtained may suggest a contribution of BDNF and glutamatergic system genes to working memory efficiency in healthy subjects and bipolar disorder, while in schizophrenia with dopaminergic system genes.

Inhibition of DNA methyltransferase activity upregulates Fyn tyrosine kinase expression in Hut-78 T-lymphoma cells

Tyrosine kinase Fyn, the expression of which is epigenetically regulated, has been proposed to be a tumour suppressor gene. A frequent deletion at the 6q chromosomal region encoding the Fyn gene in lymphomas has been reported. Therefore, we assessed the impact of 5-Aza-2′-deoxycytidine (5-dAzaC), a DNA methyltransferase (DNMTs) inhibitor on Fyn expression in Hut-78 T-lymphoma cells. Using reverse transcription, real-time quantitative PCR (RQ-PCR), and western blot analyses, we found that 5-dAzaC significantly increased transcript and protein levels of Fyn in Hut-78 T-lymphoma cells. However, bisulfite sequencing revealed that Hut-78 T-lymphoma cells cultured in the absence of 5-dAzaC contained unmethylated cytosine in the cytosine-guanosine dinucleotide island of the Fyn promoter. Our results suggest that the DNMTs activity may have an indirect influence on the expression of Fyn without altering the methylation level of its promoter in Hut-78 T-lymphoma cells.

Association Analysis of Tyrosine Kinase FYN Gene Polymorphisms in Asthmatic Children

Background: FYN is nonreceptor tyrosine kinase that represents the earliest detectable signaling response after antigen-activated inflammatory cells. Studies in animal models of allergic asthma have shown that inhibitors of tyrosine kinases exert an anti-inflammatory effect. In the FYN gene, several polymorphisms have been described. There have, however, been no studies analyzing the impact of FYN gene polymorphisms on the course and severity of asthma. The aim of this study was to analyze the possible relationship between three polymorphisms (–93A/G, Intron10+37C/T and Ex12+894T/G) in the FYN gene and asthma. Methods: We analyzed 120 pediatric asthmatic patients aged from 6 to 18 years. The diagnosis of allergic asthma was based on clinical manifestation, lung function test and positive skin prick tests and/or an increased IgE level. The control group consisted of 187 healthy subjects. The polymorphisms were genotyped with use of the PCR-RFLP method. Results: We observed an association of the –93A/G polymorphism and the presence of asthma (p = 0.014 for genotypes and p = 0.019 for alleles) and in the subgroup of 55 patients with severe asthma (p = 0.042 for genotypes and p = 0.021 for alleles). We also found an association of the Ex12+894T/G polymorphism in the whole group analyzed (p = 0.067 for genotypes and p = 0.024 for alleles), but not in the subgroup with severe asthma. For the Intron10+37T/C polymorphism, we did not find a significant difference between the whole group of asthmatic patients and the control group nor between the subgroup with severe asthma and the control group. In the linkage disequilibrium analysis, we observed a modest linkage between –93A/G and Intron10+37T/C polymorphisms (lod = 18.7, D’ = 0.62, 95% CI: 0.51–0.71, r² = 0.29); however, it was not strong enough to generate any haplotypes. Conclusions: The results may suggest a relationship between the FYN polymorphisms and allergic asthma.

Polymorphisms of the Fyn kinase gene and a performance on the Wisconsin Card Sorting Test in schizophrenia

The glutamatergic system has been implicated in the pathogenesis and prefrontal cortex dysfunctions in schizophrenia. The Src-family tyrosine kinase Fyn plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate, in prefrontal cortex. We estimated an association between three polymorphisms of Fyn gene and performance on the Wisconsin Card Sorting Test, measuring prefrontal cortex functions, in 188 schizophrenic patients. Patients with T/T genotype of IVS10+T/C polymorphism and T/T genotype of Ex12+894T/G polymorphism made significantly less perseverative errors in the Wisconsin Card Sorting Test compared with patients with remaining genotypes, and obtained numerically better results in other Wisconsin Card Sorting Test domains. No significant differences in Wisconsin Card Sorting Test performance were found as to -93 A/G polymorphism. The main finding of the study is showing a relationship between polymorphisms of the Fyn gene, related to the function of glutamatergic system, and a performance on neuropsychological test of prefrontal cortex activity in schizophrenic patients.

Fyn protein tyrosine kinase as a target for antipsychotic drugs

Fyn-deficient mice were produced by inserting the β-galactosidase gene (lacZ) into the fyn gene locus. The homozygously Fyn kinase-deficient (fynz/fynz) mice exhibited stronger light aversion in the light-dark choice test and higher fear-response scores in the novelty preference and passive avoidance tests than did the heterozygously Fyn-deficient (+/fynz) mice. These results indicate that fynz/fynz mice are hyperresponsive to fear-inducing stimuli.

317 FACTORS AFFECTING PRODUCTION EFFICIENCY OF TRANSGENIC RATS BY ICSI-MEDIATED DNA TRANSFER

Successful DNA transfer via intracytoplasmic sperm injection (ICSI) was first reported in mice (Perry et al. 1999, Science 284, 1180), and was recently extended to rats (Kato et al. 2004, Mol. Reprod. Dev. 69, 153). In the present study, factors affecting the production efficiency of transgenic rats by the ICSI-mediated DNA transfer were investigated. Cauda epididymal spermatozoa from Sprague-Dawley rats were sonicated (SO) and/or frozen-thawed (FT) for tail-cutting and membrane-disrupting. The sperm heads were exposed for 1 min to different concentrations (0.02–2.5 ng/μL) of 3.0 kb EGFP DNA solution, and then microinjected into denuded F1 (Donryu × LEW) rat oocytes. The optimal concentration of EGFP DNA was 0.1 ng/μL, as determined by the in vitro developmental competence into morulae/blastocysts and the EGFP expression of the ICSI oocytes. The presumptive 1- or 2-cell stage zygotes were transferred into oviducts of pseudopregnant Wistar females, and the presence of EGFP DNA in the offspring was examined by fluorescence under the 480 nm UV light. The production efficiency of transgenic rat offspring was 2.8% (2/71 zygotes transferred), 1.6% (1/63), and 3.3% (2/61) in the oocytes into which SO-, FT-, and SO+ FT-treated sperm heads were injected, respectively. The founder transgenic rats carrying EGFP DNA transmitted the transgenes to their progeny according to the Mendelian fashion (43.8–54.8%), suggesting the stable incorporation of the transgenes into rat genomes. Four rat strains (F344, LEW, Donryu, and Sprague-Dawley) were compared for their suitability as sperm/oocyte donors in the production of transgenic rats by ICSI with SO + FT-treated and 0.1 ng/μL EGFP DNA-exposed sperm heads. The production efficiency of the transgenic rats in the Sprague-Dawley strain (8.2%, 8/98) was significantly higher than that in LEW strain (0.9%, 1/114), while those in F344 (4.3%, 4/92) and Donryu (4.4%, 5/114) strains were intermediate. Attempts were made to introduce three other DNA constructs (5.0 kb plasmid and 208 kb BAC, both with Fyn gene, and 186 kb BAC with Svet1/IRES-Cre gene) into rat genomes by ICSI with SO + FT-treated and 0.1 ng/μL DNA-exposed sperm heads. PCR analysis showed that the Fyn, Fyn/BAC, and Svet1/IRES-Cre DNA constructs were successfully introduced into Sprague-Dawley rat offspring via ICSI, with production efficiencies of 2.8% (3/109), 0.9% (1/109), and 2.4% (3/125), respectively. These results indicate that transgenic rats can be produced by ICSI-mediated DNA transfer using the various types of exogenous DNA and rat strains with different genetic backgrounds.