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Shengzhen Guo,
Jian Zhou,
Bo Gao,
Jianxin Hu,
Hongsheng Wang, Junwei Meng,
Xinzhi Zhao,
Gang Ma,
Chuwen Lin,
Yue Xiao,
Wei Tang,
Xuming Zhu,
Kathryn S E Cheah,
Guoying Feng,
Danny Chan,
Lin He
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ABSTRACT: Heterozygous missense mutations in IHH result in Brachydactyly type A1 (BDA1; OMIM 112500), a condition characterized by the shortening of digits due to hypoplasia/aplasia of the middle phalanx. Indian Hedgehog signaling regulates the proliferation and differentiation of chondrocytes and is essential for endochondral bone formation. Analyses of activated IHH signaling in C3H10T1/2 cells showed that three BDA1-associated mutations (p.E95K, p.D100E and p.E131K) severely impaired the induction of targets such as Ptch1 and Gli1. However, this was not a complete loss of function, suggesting that these mutations may affect the interaction with the receptor PTCH1 or its partners, with an impact on the induction potency. From comparative microarray expression analyses and quantitative real-time PCR, we identified three additional targets, Sostdc1, Penk1 and Igfbp5, which were also severely affected. Penk1 and Igfbp5 were confirmed to be regulated by GLI1, while the induction of Sostdc1 by IHH is independent of GLI1. SOSTDC1 is a BMP antagonist, and altered BMP signaling is known to affect digit formation. The role of Penk1 and Igfbp5 in skeletogenesis is not known. However, we have shown that both Penk1 and Igfbp5 are expressed in the interzone region of the developing joint of mouse digits, providing another link for a role for IHH signaling in the formation of the distal digits.
Cellular & Molecular Biology Letters 01/2010; 15(1):153-76. · 1.50 Impact Factor
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Baohu Ji,
Yujuan La,
Linghan Gao,
Hui Zhu,
Nan Tian,
Ming Zhang,
Yifeng Yang,
Xinzhi Zhao,
Ruqi Tang,
Gang Ma,
Jian Zhou, Junwei Meng,
Jie Ma,
Zhao Zhang,
Huafang Li,
Guoyin Feng,
Yujiong Wang,
Lin He,
Chunling Wan
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ABSTRACT: An increasing number of experiments have found anomalies in mitochondria in the brains of psychotics, which suggests that mitochondrial dysfunction or abnormal cerebral energy metabolism might play an important role in the pathophysiology of schizophrenia (SCZ). We adopted a proteomic approach to identify the differential effects on the cerebral cortex and hippocampus mitochondrial protein expression of Sprague-Dawley (SD) rats by comparing exposure to typical and atypical antipsychotic medications. Differential mitochondrial protein expressions were assessed using two-dimensional (2D) gel electrophoresis for three groups with Chlorpromazine (CPZ), Clozapine (CLZ), quetiapine (QTP) and a control group. A total of 14 proteins, of which 6 belong to the respiratory electron transport chain (ETC) of oxidative phosphorylation (OXPHOS), showed significant changes in quantity including NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 10 (Ndufa10), NADH dehydrogenase (ubiquinone) flavoprotein 2 (Ndufv2), NADH dehydrogenase (ubiquinone) Fe-S protein 3 (Ndufs3), F1-ATPase beta subunit (Atp5b), ATPase, H+ transporting, lysosomal, beta 56/58 kDa, isoform 2 (Atp6v1b2) and ATPase, H+ transporting, V1 subunit A, isoform 1 (Atp6v1a1). The differential proteins subjected to 2D were assessed for levels of mRNA using quantitative real time PCR (Q-RT-PCR), and we also made partial use of Western blotting for assessing differential expression. The results of our study may help to explain variations in SD rats as well as in human response to antipsychotic drugs. In addition, they should improve our understanding of both the curative effects and side effects of antipsychotics and encourage new directions in SCZ research.
Journal of Proteome Research 06/2009; 8(7):3633-41. · 5.11 Impact Factor
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ABSTRACT: Schizophrenia is a chronic psychiatry disorder with a strong genetic component. A recent association study of alpha(1A)-adrenoceptor gene (ADRA1A) involving an isolated Spanish population, focusing on the promoter region of the ADRA1A, genotyped eight single SNPs at the promoter region of ADRA1A and found that two SNPs, -563G/A and -9625G/A, were associated with schizophrenia and schizoaffective disorders. We were interested in the two positive sites reported and selected five variants among the promoter region of ADRA1A, namely -563G/A, -9625G/A, -2760C/A, -4155G/C and a new substitution we detected between -508bp and -530bp upstream of the translation initiation site. Our sample consisted of 480 schizophrenia and 480 control subjects. All recruits were Han Chinese in Shanghai origin. However, neither individual SNP nor any haplotype was associated with schizophrenia in our study. These results suggest that the variants among the promoter of ADRA1A gene are unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population.
Journal of Psychiatric Research 05/2008; 42(5):384-8. · 4.66 Impact Factor
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Junwei Meng,
Yongyong Shi,
Xinzhi Zhao,
Jian Zhou,
Yonglan Zheng,
Ruqi Tang,
Gang Ma,
Xuming Zhu,
Zangdong He,
Zhe Wang,
Yifeng Xu,
Guoyin Feng,
Lin He
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ABSTRACT: The GSK-3 beta gene encodes a protein kinase which is abundant in the brain, and its product is involved in signal transduction cascades of neuronal cell development, energy metabolism and body pattern formation. Previous studies have suggested that GSK-3 beta might act as a potential candidate locus for schizophrenia susceptibility. We genotyped six SNPs within the gene and conducted a case-control study involving 329 schizophrenic patients and 288 healthy subjects in the Chinese population. We examined allele and genotype frequencies and haplotype distributions in the subtype of paranoid schizophrenic patients as well as schizophrenic subjects in general. Our results fail to replicate the association of the GSK-3 beta gene with susceptibility to schizophrenia in the Chinese population.
Journal of Psychiatric Research 05/2008; 42(5):365-70. · 4.66 Impact Factor
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ABSTRACT: Suicide is a significant health problem throughout the world. The serotoninergic system is believed to be involved in suicidal behavior and there is evidence of biological abnormalities of two serotonin receptors (HTR2A, HTR2C) and one serotonin transporter (5HTT) in suicide victims. Rs6313 (T102C) of HTR2A and rs6318 (Cys23Ser) of HTR2C have been investigated in suicide behavior in other studies.
Here, we investigated rs6313 and rs6318 and other 10 randomly chosen SNPs, of those three genes in a study of 329 psychiatric patients who had never attempted suicide and 297 patients who had attempted suicide.
No associations were found for the 12 SNPS.
Our results do not support the involvement of HTR2A, 5HTT or HTR2C in suicidal behavior in Han Chinese subjects.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2008; 32(2):467-71. · 3.25 Impact Factor
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Jian Zhou, Junwei Meng,
Shengzhen Guo,
Bo Gao,
Gang Ma,
Xuming Zhu,
Jianxin Hu,
Yue Xiao,
Chuwen Lin,
Hongsheng Wang,
Lusheng Ding,
Guoyin Feng,
Xizhi Guo,
Lin He
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ABSTRACT: In the developing limb bud, digit pattern arises from anterior-posterior (A-P) positional information which is provided by the concentration gradient of SHH. However, the mechanisms of translating early asymmetry into morphological form are still unclear. Here, we examined the ability of IHH and FGF8 signaling to regulate digital chondrogenesis, by implanting protein-loaded beads in the interdigital space singly and in combination. We found that IHH protein induced an elongated digit and that FGF8 protein blocked the terminal phalange formation. Molecular marker analysis showed that IHH expanded Sox9 expression in mesenchymal cells possibly through up-regulated FGF8 expression. Application of both IHH and FGF8 protein induced a large terminal phalange. These results suggest that both enhanced IHH and FGF8 signaling are required for the development of additional cartilage element in limbs. IHH and FGF8 maybe play different roles and act synergistically to promote chondrogenesis during digit primordia elongation.
Biochemical and Biophysical Research Communications 12/2007; 363(3):513-8. · 2.48 Impact Factor
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Qinghe Xing,
Xueqing Qian,
Huafang Li,
Shiming Wong,
Shengnan Wu,
Guoyin Feng,
Shiwei Duan,
Mingqing Xu,
Rui Gao,
Wei Qin,
Jianjun Gao, Junwei Meng,
Lin He
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ABSTRACT: Antipsychotic drugs exert both therapeutic and adverse effects through dopamine D2 receptor (DRD2) antagonism. Genetic variants of this receptor may be responsible for individual variations in neuroleptic response and may therefore be useful in predicting response. In this study we evaluated the role of six polymorphisms of the DRD2 gene in 125 risperidone-treated Chinese schizophrenia patients following the hypothesis that variation in the DRD2 gene could affect drug response. Response was categorized as a change of >40% on the Brief Psychiatric Rating Scale (BPRS). Our results show that genotyping A-241G may help to predict the efficacy of risperidone treatment on the basis that patients with the A allele showed greater improvement than those with the G allele on the overall BPRS (chi2=7.19, p=0.007, p=0.031 after correction by the program SNPSpD), while other polymorphisms, including -141C Ins/Del, TaqIB, rs1076562, T939C and TaqIA, did not show any association with the response to risperidone. These data suggest that the DRD2 A-241G polymorphism or, alternatively, another genetic variation that is in linkage disequilibrium, may influence response to risperidone in schizophrenia patients.
The International Journal of Neuropsychopharmacology 10/2007; 10(5):631-7. · 4.58 Impact Factor
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ZangDong He,
ZhiQiang Li,
YongYong Shi,
Wei Tang,
Ke Huang,
Gang Ma,
Jian Zhou, JunWei Meng,
HuaFang Li,
GuoYing Feng,
Lin He
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ABSTRACT: Results from a number of molecular and pharmacological studies suggest that the phosphatidylinositol-4-phosphate 5-kinase IIalpha (PIP5K2A) gene may be involved in the development of schizophrenia. A recent family-based transmission disequilibrium test in the German and Israeli populations found that four single nucleotide polymorphisms, rs1417374, rs10828317, rs746203 and rs8341 in this gene or nearby intergenic regions are significantly associated with schizophrenia. The objective of our study was to investigate whether these four SNPs are also associated with schizophrenia in the Chinese population. Our study found that SNP rs8341 (p=0.0045, Odds Ratio=1.415, 95%CI=1.113-1.799 for the minor allele) and a haplotype (p=0.0039, Odds Ratio=1.440, 95%CI=1.123-1.845) are significantly associated with schizophrenia. Our results confirm that the PIP5K2A gene merits further study as a susceptible gene for schizophrenia.
Schizophrenia Research 09/2007; 94(1-3):359-65. · 4.75 Impact Factor
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Jing Du,
Yongyong Shi,
Aiping Zhang,
Lei Wang,
Jiekun Xuan,
Guang He,
Lingyun Xu,
Mingsheng Xu,
Anli Shu,
Lan Yu,
Xingwang Li, Junwei Meng,
Guoyin Feng,
Qinghe Xing,
Lin He
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ABSTRACT: To determine the frequencies and haplotypes of the cytochrome P450 (CYP)3A7 gene in three Chinese ethnic groups, namely, Han, She and Dong.
SNP analyses of the CYP3A7 gene were carried out on three groups of healthy Chinese subjects consisting of 539 Han, 264 She and 273 Dong subjects, using direct sequencing. Linkage disequilibrium, haplotype inference and Hardy-Weinberg equilibrium were also determined for these samples.
Significant differences were observed in the distribution of SNP rs2257401 (CYP3A7*2), SNP 1227 T>C (Novel), SNP rs4646468 and SNP rs10211 between the Han, She and Dong groups.
Some allele and haplotype frequencies show variation among groups, highlighting the need to analyze clinically relevant SNPs and haplotypes in a variety of different racial groups within the Chinese population as well as in other ethnic groups. These results suggest that genetic polymorphisms in the CYP3A7 gene in the Han, She and Dong populations may contribute to interindividual as well as intra-ethnic differences in response to the clearance of CYP3A7 substrates.
Pharmacogenomics 06/2007; 8(6):559-66. · 3.97 Impact Factor
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Xinzhi Zhao,
Ruqi Tang,
Bo Gao,
Yongyong Shi,
Jian Zhou,
Shengzhen Guo,
Jing Zhang,
Yabing Wang,
Wei Tang, Junwei Meng, [......],
Gang Ma,
Chuwen Lin,
Yue Xiao,
Guoyin Feng,
Zhiguang Lin,
Shaomin Zhu,
Yangling Xing,
Hong Sang,
David St Clair,
Lin He
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ABSTRACT: The chitinase 3-like 1 gene (CHI3L1) is abnormally expressed in the hippocampus of subjects with schizophrenia and may be involved in the cellular response to various environmental events that are reported to increase the risk of schizophrenia. Here, we provide evidence that the functional variants at the CHI3L1 locus influence the genetic risk of schizophrenia. First, using case-control and transmission/disequilibrium-test (TDT) methodologies, we detected a significant association between schizophrenia and haplotypes within the promoter region of CHI3L1 in two independent cohorts of Chinese individuals. Second, the at-risk CCC haplotype (P=.00058 and .0018 in case-control and TDT studies, respectively) revealed lower transcriptional activity (P=2.2 x 10(-7)) and was associated with lower expression (P=3.1 x 10(-5)) compared with neutral and protective haplotypes. Third, we found that an allele of SNP4 (rs4950928), the tagging SNP of CCC, impaired the MYC/MAX-regulated transcriptional activation of CHI3L1 by altering the transcriptional-factor consensus sequences, and this may be responsible for the decreased expression of the CCC haplotype. In contrast, the protective TTG haplotype was associated with a high level of CHI3L1 expression. Our findings identify CHI3L1 as a potential schizophrenia-susceptibility gene and suggest that the genes involved in the biological response to adverse environmental conditions are likely to play roles in the predisposition to schizophrenia.
The American Journal of Human Genetics 02/2007; 80(1):12-8. · 10.60 Impact Factor
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ABSTRACT: P-glycoprotein, a product of the ATP-binding cassette B1 (ABCB1) gene, plays an important role in absorption and distribution of drugs. The brain entry of risperidone and 9-OH-risperidone is greatly limited by P-glycoprotein, which implies that the functional polymorphisms of ABCB1 in humans may be a factor contributing to the variability in response to risperidone. The present study was therefore designed to examine whether polymorphisms of the ABCB1 gene are related to therapeutic response. For this purpose, 130 Chinese schizophrenia patients undergoing risperidone treatment were recruited. Plasma drug concentrations were monitored and clinical symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS) before and 8 weeks after the treatment. Association tests between genotypes and percentage improvement in total BPRS scores were performed using analyses of variance. Our results show that genotyping C1236T may help to predict the efficacy of risperidone treatment on the basis that patients with the TT genotype showed greater improvement than those with other genotypes on the overall BPRS (F = 3.967, p = 0.021), while other polymorphisms, including rs13233308, G2677T/A and C3435T polymorphism, did not show any association with the response to risperidone. These results showed suggestive evidence that genetic variation in the ABCB1 gene may influence the individual response to risperidone.
Pharmacogenomics 11/2006; 7(7):987-93. · 3.97 Impact Factor
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Shengzhen Guo,
Yongyong Shi,
Xinzhi Zhao,
Shiwei Duan,
Jian Zhou, Junwei Meng,
Yifeng Yang,
Niufan Gu,
Guoyin Feng,
Huijun Liu,
Shaomin Zhu,
Lin He
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ABSTRACT: The glutamatergic dysfunction hypothesis of schizophrenia suggests genes involved in glutamatergic transmission as candidates for schizophrenia-susceptibility genes. It has recently been reported that some haplotypes in the AMPA receptor subunit GluR4 Gene (GRIA4), which is located on chromosome 11q22, are positively associated with schizophrenia in the Japanese population. In order to assess the role of GRIA4 in schizophrenia, we examined three reported positive SNPs (single nucleotide polymorphisms): rs609239, rs641574 and rs659840 at the GRIA4 locus in schizophrenic cases (n = 372) and controls (n = 392) of the Chinese population. Although we had observed similar allele and genotype frequencies compared with that in the Japanese population, no evidence was found for association with the disease in the analysis of either single nucleotide polymorphisms (all P-values > 0.300) or haplotype relative risk (all P-values > 0.088). Our results suggest that the three SNPs of GRIA4 are unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population.
Neuroscience Letters 10/2004; 369(2):168-72. · 2.11 Impact Factor
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Qinghe Xing,
Anli Shu,
Lan Yu,
Aiping Zhang,
Jing DU,
Jiekun Xuan,
Lei Wang,
Guang He, Junwei Meng,
Xingwang Li,
Guoyin Feng,
Lin He
European journal of dermatology: EJD 17(3):247-8. · 2.53 Impact Factor
