NeuroMolecular Medicine

, Volume 20, Issue 3, pp 401–408 | Cite as

Potential Role of Brain-Derived Neurotrophic Factor and Dopamine Receptor D2 Gene Variants as Modifiers for the Susceptibility and Clinical Course of Wilson’s Disease

  • Shubhrajit Roy
  • Prosenjit Pal
  • Sampurna Ghosh
  • Sreyashi Bhattacharya
  • Shyamal Kumar Das
  • Prasanta Kumar Gangopadhyay
  • Ashish Bavdekar
  • Kunal Ray
  • Mainak SenguptaEmail author
  • Jharna RayEmail author
Original Paper


Wilson’s disease (WD), an inborn error of copper metabolism caused by mutations in the ATPase copper transporting beta (ATP7B) gene, manifests variable age of onset and different degrees of hepatic and neurological disturbances. This complex phenotypical outcome of a classical monogenic disease can possibly be explained by modifier loci regulating the clinical course of the disease. The brain-derived neurotropic factor (BDNF), critical for the survival, morphogenesis, and plasticity of the neurons, and the dopamine receptor D2 (DRD2), one of the most abundant dopamine receptors in the brain, have been highlighted in the pathophysiology of various neuropsychiatric diseases. This study aims to identify the potential association between BDNF and DRD2 gene polymorphisms and WD and its clinical characteristics. A total of 164 WD patients and 270 controls from India were included in this study. Two BDNF polymorphisms [p.Val66Met (c.G196A) and c.C270T] and the DRD2 Taq1A (A2/A1 or C/T) polymorphism were examined for their association with WD and some of its clinical attributes, using polymerase chain reaction, restriction fragment length digestion, and bidirectional sequencing. The C allele and CC genotype of BDNF C270T were significantly overrepresented among controls compared to WD patients. In addition, a significantly higher proportion of the allele coding for Val and the corresponding homozygous genotype of BDNF Val66Met polymorphism was found among WD patients with age of onset later than 10 years. Furthermore, the A1A1 genotype of DRD2 Taq1A polymorphism was significantly more common among WD patients with rigidity. Our data suggest that both BDNF and DRD2 may act as potential modifiers of WD phenotype in the Indian context.


BDNF DRD2 Wilson’s disease WD 



We are thankful to the Wilson’s disease patients and their family members for participating in this study. The study was partially supported by the funding from Department of Science & Technology Cognitive Sciences Research Initiative (DST-CSRI), Govt. of India. SR is supported by UGC-JRF fellowship from UGC, Govt. of India, PP is supported by University Research Fellowship, and SG had been supported by a fellowship from DST-SERB, Govt. of India.

Author Contributions

SR: PCR-RFLP and sequencing of BDNF (Val66Met and C270T) and DRD2 gene among WD patients (Val66Met, 164 samples, C270T 104 samples, DRD2, 142 samples), analysis of the result, and drafting of the manuscript. PP: PCR-RFLP of BDNF Val66Met and C270T among 270 controls. SG: PCR-RFLP for BDNF, C270T, and DRD2 among WD samples (BDNF, 60 samples, DRD2, 20 samples). SB: PCR-RFLP for DRD2 among control samples (50 samples). MSG: Involved in study design, experimental details, and writing of the manuscript. KR: A senior investigator in WD project provided intellectual input and preparation of the manuscript. JR: Principle Investigator of the project provided intellectual input and involved in preparation of the manuscript. SKD, PKG, AB: Patient recruitment, clinical evaluation, and blood sample collection from patients from Kolkata area.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest with respect to this article.

Supplementary material

12017_2018_8501_MOESM1_ESM.docx (12 kb)
Supplementary material 1 (DOCX 12 KB)
12017_2018_8501_MOESM2_ESM.docx (15 kb)
Supplementary material 2 (DOCX 11 KB)
12017_2018_8501_MOESM3_ESM.xlsx (24 kb)
Supplementary material 3 (XLSX 24 KB)
12017_2018_8501_MOESM4_ESM.docx (18 kb)
Supplementary material 4 (DOCX 18 KB)


  1. Autry, A. E., & Monteggia, L. M. (2012). Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacological Reviews, 64(2), 238–258.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Blum, K., Badgaiyan, R. D., Dunston, G. M., et al. (2017). The DRD2 Taq1A A1 allele may magnify the risk of alzheimer’s in aging African-Americans. Molecular Neurobiology. Scholar
  3. Cartharius, K., Frech, K., Grote, K., et al. (2005). MatInspector and beyond: Promoter analysis based on transcription factor binding sites. Bioinformatics, 21(13), 2933–2942.CrossRefPubMedGoogle Scholar
  4. Członkowska, A., Jachowicz-Jeszka, J., & Członkowski, A. (1987). [3H] Spiperone binding to lymphocyte in extrapyramidal disease and in aging. Brain, Behavior and Immunity, 1(3), 197–203.CrossRefGoogle Scholar
  5. Das, S. K., & Ray, K. (2006). Wilson’s disease: An update. Nature Review Neurology, 2(9), 482.Google Scholar
  6. De Vries, D. J., Sewell, R. B., & Beart, P. M. (1986). Effects of copper on dopaminergic function in the rat corpus striatum. Experimental Neurology, 91(3), 546–558.CrossRefPubMedGoogle Scholar
  7. Egan, M. F., Kojima, M., Callicott, J. H.,et al (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112(2), 257–269.CrossRefPubMedGoogle Scholar
  8. Gallati, S. (2014). Disease-modifying genes and monogenic disorders: Experience in cystic fibrosis. The Application of Clinical Genetics., 7, 133–146.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Genzer, Y., Chapnik, N., & Froy, O. (2014). Effect of brain-derived neurotrophic factor (BDNF) on hepatocyte metabolism. International Journal of Biochemistry and Cell Biology, 88, 69–74.CrossRefGoogle Scholar
  10. Glatt, S. J., Faraone, S. V., & Tsuang, M. T. (2003). Meta-analysis identifies an association between the dopamine D2 receptor gene and schizophrenia. Molecular Psychiatry, 8(11), 911.CrossRefPubMedGoogle Scholar
  11. Grillo, E., Rizzo, C. L., Bianciardi, al. (2013). Revealing the complexity of a monogenic disease: Rett syndrome exome sequencing. PLoS ONE 8(2), e56599.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Gupta, A., Chattopadhyay, I., Mukherjee, S., Sengupta, M., Das, S. K., & Ray, K. (2010). A novel COMMD1 mutation Thr174Met associated with elevated urinary copper and signs of enhanced apoptotic cell death in a Wilson Disease patient. Behavioral and Brain Functions, 6(1), 33.CrossRefPubMedGoogle Scholar
  13. Kegley, K. M., Sellers, M. A., Ferber, M. J., Johnson, M. W., Joelson, D. W., & Shrestha, R. (2010). Fulminant Wilson’s disease requiring liver transplantation in one monozygotic twin despite identical genetic mutation. American Journal of Transplantation, 10(5), 1325–1329.CrossRefPubMedGoogle Scholar
  14. Kieffer, D. A., & Medici, V. (2017). Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence. Liver Research, 1(2), 121–130.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Klein, C., Brin, M. F., Kramer, P., et al. (1999) Association of a missense change in the D2 dopamine receptor with myoclonus dystonia. Proceedings of the National Academy of Science USA, 96, 5173–5176.CrossRefGoogle Scholar
  16. Travaglia, A., La Mendola, D., Magrì, A., Nicoletti, V. G., Pietropaolo, A., Rizzarelli,  E. (2012). Copper, BDNF and its N-terminal domain: Inorganic features and biological perspectives. Chemistry–A European Journal, 18(49), 15618–15631.CrossRefGoogle Scholar
  17. Mizui, T., Ishikawa, Y., Kumanogoh, H., et al. (2015). BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met. Proceedings of the National Academy of Sciences, 112(23), E3067–E3074.CrossRefGoogle Scholar
  18. Mizui, T., Ohira, K., & Kojima, M. (2017). BDNF pro-peptide: a novel synaptic modulator generated as an N-terminal fragment from the BDNF precursor by proteolytic processing. Neural Regeneration Research, 12(7), 1024.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Mizui, T., Tanima, Y., Komatsu, H., Kumanogoh, H., & Kojima, M. (2014). The biological actions and mechanisms of brain-derived neurotrophic factor in healthy and disordered brains. Neuroscience and Medicine, 5(04), 183.CrossRefGoogle Scholar
  20. Mukherjee, S., Dutta, S., Majumdar, S.,et al (2014). Genetic defects in Indian Wilson disease patients and genotype–phenotype correlation. Parkinsonism and Related Disorder, 20(1), 75–81.CrossRefGoogle Scholar
  21. Munafo, M. R., Matheson, I. J., & Flint, J. (2007). Association of the DRD2 gene Taq1A polymorphism and alcoholism: A meta-analysis of case–control studies and evidence of publication bias. Molecular Psychiatry, 12(5), 454.CrossRefPubMedGoogle Scholar
  22. Noble, E. P. (2000). Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: A review. European Psychiatry, 15(2), 79–89.CrossRefPubMedGoogle Scholar
  23. Noble, E. P. (2003). D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 116(1), 103–125.CrossRefGoogle Scholar
  24. Nyberg, P., Gottfries, C. G., Holmgren, G., Persson, S., Roos, B. E., & Winblad, B. (1982). Advanced catecholaminergic disturbances in the brain in a case of Wilson’s disease. Acta Neurologica Scandinavica, 65(1), 71–75.CrossRefPubMedGoogle Scholar
  25. Oder, W., Brücke, T., Kollegger, H., Spatt, J., Asenbaum, S., & Deecke, L. (1996). Dopamine D2 receptor binding is reduced in Wilson’s disease: Correlation of neurological deficits with striatal 123 I-Iodobenzamide binding. Journal of Neural Transmission, 103(8–9), 1093–1103.CrossRefPubMedGoogle Scholar
  26. Przybyłkowski, A., Gromadzka, G., & Członkowska, A. (2014). Polymorphisms of metal transporter genes DMT1 and ATP7A in Wilson’s disease. Journal of Trace Elements in Medicine and Biology, 28(1), 8–12.CrossRefPubMedGoogle Scholar
  27. Rowe, D. C., Van den Oord, E. J., Stever, C.,et al (1999). The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder. Molecular Psychiatry, 4(6), 580.CrossRefPubMedGoogle Scholar
  28. Roy, S., Ganguly, K., Pal, P., et al. (2017). Influence of Apolipoprotein E polymorphism on susceptibility of Wilson disease. Annals of Human Genetics, 82(2), 53–59.CrossRefPubMedGoogle Scholar
  29. Sternlieb, I. (1990). Perspectives on Wilson’s disease. Hepatology, 12(5), 1234–1239.CrossRefPubMedGoogle Scholar
  30. Todorov, T., Balakrishnan, P., Savov, A., Socha, P., & Schmidt, H. H. (2016). Intragenic deletions in ATP7B as an unusual molecular genetics mechanism of Wilson’s disease pathogenesis. PLoS ONE, 11(12), e0168372.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Watanabe, Y., Nunokawa, A., & Someya, T. (2013). Association of the BDNF C270T polymorphism with schizophrenia: UFated meta-analysis. Psychiatry and Clinical Neuroscience, 67(2), 123–125.CrossRefGoogle Scholar
  32. Westermark, K., Tedroff, J., Thuomas, K. A., et al. (1995). Neurological Wilson’s disease studied with magnetic resonance imaging and with positron emission tomography using dopaminergic markers. Movement Disorders, 10(5), 596–603.CrossRefPubMedGoogle Scholar
  33. Xu, C., Wang, Z., Fan, M.,et al (2010). Effects of BDNF Val66Met polymorphism on brain metabolism in Alzheimer’s disease. NeuroReport, 21(12), 802.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.S. N. Pradhan Centre for NeurosciencesUniversity of CalcuttaKolkataIndia
  2. 2.Department of GeneticsUniversity of CalcuttaKolkataIndia
  3. 3.Bangur Institute of NeurosciencesKolkataIndia
  4. 4.Calcutta National Medical CollegeKolkataIndia
  5. 5.KEM HospitalPuneIndia
  6. 6.Academy of Scientific and Innovative Research (AcSIR)New DelhiIndia

Personalised recommendations