Journal Mobile Options
Table of Contents
Vol. 50, No. 3, 2004
Issue release date: September 2004
Neuropsychobiology 2004;50:206–210

Analysis of Enhancer Activity of a Dinucleotide Repeat Polymorphism in the Neurotrophin-3 Gene and Its Association with Bipolar Disorder

Tadokoro K. · Hashimoto R. · Tatsumi M. · Kamijima K. · Kunugi H.
aDepartment of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Ogawahigashi, Kodaira, and bDepartment of Psychiatry, Showa University School of Medicine, Tokyo, Japan

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Growing evidence has implicated the possible involvement of neurotrophins in the pathogenesis of functional psychoses such as schizophrenia and bipolar disorder. Previous studies reported a significant association of a dinucleotide repeat polymorphism of the neurotrophin-3 (NTF3) gene with schizophrenia. The aims of the present study were to examine whether this polymorphism is associated with bipolar disorder and whether the polymorphic region has an enhancer/silencer effect on transcriptional activity in an allele-dependent manner. In an association analysis between the polymorphism and bipolar disorder in a Japanese sample of 88 patients and 98 controls matched for age, sex, and ethnicity, the distribution of alleles did not differ significantly between the two groups. pGL3-promoter luciferase reporter vectors containing the polymorphic region increased luciferase activity relative to empty pGL3-promoter vector in HeLa, IMR-32 (neuroblastoma) and Hs683 (glioma) cell lines; however, no significant difference was detected between alleles for either cell line. Our results suggest that the examined polymorphism has no major role in giving susceptibility to bipolar disorder. Although the polymorphic region may have an enhancer-like effect on transcriptional activity, we obtained no evidence for allele-dependent differential effects.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Thome J, Foley P, Riederer P: Neurotrophic factors and the maldevelopmental hypothesis of schizophrenic psychoses. J Neural Transm 1998;105:85–100.
  2. Duman RS: Synaptic plasticity and mood disorders. Mol Psychiatry 2002;7(suppl 1):S29–S34.
  3. Maisonpierre PC, Le Beau MM, Espinosa R III, Ip NY, Belluscio L, de la Monte SM, Squinto S, Furth ME, Yancopoulos GD: Human and rat brain-derived neurotrophic factor and neurotrophin-3:Gene structures, distributions, and chromosomal localizations. Genomics 1991;10:558–568.
  4. Hattori M, Kuwata S, Fukuda R, Sasaki T, Shibata Y, Kazamatsuri H, Nanko S: Dinucleotide repeat polymorphism in the promoter region of neurotrophin-3 gene (NT3). Hum Mol Genet 1993;2:1511.
  5. Nanko S, Hattori M, Kuwata S, Sasaki T, Fukuda R, Dai XY, Yamaguchi K, Shibata Y, Kazamatsuri H: Neurotrophin-3 gene polymorphism associated with schizophrenia. Acta Psychiatr Scand 1994;89:390–392.
  6. Dawson E, Powell JF, Sham PC, Nothen M, Crocq MA, Propping P, Korner J, Rietschel M, van Os J, Wright P, Murray RM, Gill M: An association study of a neurotrophin-3 (NT-3) gene polymorphism with schizophrenia. Acta Psychiatr Scand 1995;92:425–428.
  7. Jonsson E, Brene S, Zhang XR, Nimgaonkar VL, Tylec A, Schalling M, Sedvall G: Schizophrenia and neurotrophin-3 alleles. Acta Psychiatr Scand 1997;95:414–419.
  8. Virgos C, Martorell L, Valero J, Figuera L, Civeira F, Joven J, Labad A, Vilella E: Association study of schizophrenia with polymorphisms at six candidate genes. Schizophr Res 2001;49:65–71.
  9. Hattori M, Kunugi H, Akahane A, Tanaka H, Ishida S, Hirose T, Morita R, Yamakawa K, Nanko S: Novel polymorphisms in the promoter region of the neurotrophin-3 gene and their associations with schizophrenia. Am J Med Genet 2002;114:304–309.
  10. Nimgaonkar VL, Zhang XR, Brar JS, DeLeo M, Ganguli R: Lack of association of schizophrenia with the neurotrophin-3 gene locus. Acta Psychiatr Scand 1995;92:464–466.
  11. Arinami T, Takekoshi K, Itokawa M, Hamaguchi H, Toru M: Failure to find associations of the CA repeat polymorphism in the first intron and the Gly-63/Glu-63 polymorphism of the neurotrophin-3 gene with schizophrenia. Psychiatr Genet 1996;6:13–15.
  12. Gill M, Hawi Z, O’Neill FA, Walsh D, Straub RE, Kendler KS: Neurotrophin-3 gene polymorphisms and schizophrenia: No evidence for linkage or association. Psychiatr Genet 1996;6:183–186.
  13. Kunugi H, Hattori M, Nanko S, Fujii K, Kato T, Nanko S: Dinucleotide repeat polymorphism in the neurotrophin-3 gene and hippocampal volume in psychoses. Schizophr Res 1999;37:271–273.
  14. Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G, Schaffner S, Kirov G, Jones I, Owen M, Craddock N, DePaulo JR, Lander ES: Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neurotrophic factor. Mol Psychiatry 2002;7:579–593.
  15. Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL: The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: Evidence from a family-based association study. Am J Hum Genet 2002;71:651–655.
  16. Berrettini W: Evidence for shared susceptibility in bipolar disorder and schizophrenia. Am J Med Genet 2003;123C:59–64.
  17. Comings DE: Polygenic inheritance and micro/minisatellites. Mol Psychiatry 1998;3:21–31.
  18. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4. Washington, American Psychiatric Association, 1994.
  19. Shintani A, Ono Y, Kaisho Y, Sasada R, Igarashi K: Identification of the functional regulatory region of the neurotrophin-3 gene promoter. Brain Res Mol Brain Res 1993;17:129–134.
  20. Leingartner A, Lindholm D: Two promoters direct transcription of the mouse NT-3 gene. Eur J Neurosci 1994;6:1149–1159.
  21. Sham PC, Curtis D: Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 1995;59:97–105.

    External Resources

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50