Top

BMC Medical Genetics

Published in:

Open Access 01-12-2008 | Research article

DNA methylation and mRNA expression of SYN III, a candidate gene for schizophrenia

Authors: Brenda C Murphy, Richard L O'Reilly, Shiva M Singh

Published in: BMC Medical Genetics | Issue 1/2008

Abstract

Background

The synapsin III (SYN III) gene on chromosome 22q is a candidate gene for schizophrenia susceptibility due to its chromosome location, neurological function, expression patterns and functional polymorphisms.

Methods

This research has established the mRNA expression of SYN III in 22 adult human brain regions as well as the methylation specificity in the closest CpG island of this gene. The methylation specificity studied in 31 brain regions (from a single individual) was also assessed in 51 human blood samples (representing 20 people affected with schizophrenia and 31 normal controls) including a pair of monozygotic twin discordant for schizophrenia and 2 non-human primates.

Results

The results show that the cytosine methylation in this genomic region is 1) restricted to cytosines in CpG dinucleotides 2) similar in brain regions and blood and 3) appears conserved in primate evolution. Two cytosines (cytosine 8 and 20) localized as the CpG dinucleotide are partially methylated in all brain regions studied. The methylation of these sites in schizophrenia and control blood samples was variable. While cytosine 8 was partially methylated in all samples, the distribution of partial to complete methylation at the cytosine 20 was 22:9 in controls as compared to 18:2 in schizophrenia (p = 0.82). Also, there is no difference in methylation between the affected and unaffected member of a monozygotic twin pair.

Conclusion

The variation in SYN III methylation studied is 1) not related to schizophrenia in the population sample or a monozygotic twin pair discordant for schizophrenia and 2) not related to the mRNA level of SYN IIIa in different human brain regions.

Available only for authorised users

Evergren E, Benfenati F, Shupliakov O: The synapsin cycle: A view from the synaptic endocytic zone. J Neurosci Res. 2007, 85: 2648-2656. 10.1002/jnr.21176.CrossRefPubMed

Kao H, Porton B, Czernik AJ, Feng J, Yiu G, Haring M, Benfenati F, Greengard P: A third member of the synapsin gene family. Proc Natl Acad Sci USA. 1998, 95: 4667-4672. 10.1073/pnas.95.8.4667.CrossRefPubMedPubMedCentral

Porton B, Kao H, Greengard P: Characterization of transcripts from the synapsin III gene locus. J of Neurochem. 1999, 73: 2266-2271. 10.1046/j.1471-4159.1999.0732266.x.CrossRef

Ferreira A, Rapoport M: The synapsins: beyond the regulation of neurotransmitter release. Cell Mol Life Sci. 2002, 59: 589-595. 10.1007/s00018-002-8451-5.CrossRefPubMed

Stober G, Meyer J, Nanda I, Wienker TF, Saar K, Knapp M, Jatzke S, Schmid M, Lesch KP, Beckmann H: Linkage and family-based association study of schizophrenia and the synapsin III locus that maps to chromosome 22q13. Am J Med Genet. 2000, 96: 392-397. 10.1002/1096-8628(20000612)96:3<392::AID-AJMG29>3.0.CO;2-R.CrossRefPubMed

Ohtsuki T, Ichiki R, Toru M, Arinami T: Mutational analysis of the synapsin III gene on chromosome 22q12-q13 in schizophrenia. Psychiatry Res. 2000, 94: 1-7. 10.1016/S0165-1781(00)00123-2.CrossRefPubMed

Ohmori O, Shinkai T, Hori H, Kojima H, Nakamura J: Synapsin III gene polymorphisms and schizophrenia. Neuroscience Letters. 2000, 279: 125-127. 10.1016/S0304-3940(99)00970-2.CrossRefPubMed

Imai K, Harada S, Kawanish Y, Tachikawa H, Okubo T, Susuki T: Polymorphisms in the promoter an coding regions of the synapsin III gene. Neurospychobiology. 2001, 43: 237-241. 10.1159/000054896.

Tsai MT, Hung CC, Tsai CY, Liu MY, Su YC, Chen YH, Hsiaso KJ, Chen CH: Mutation analysis of synapsin III gene in schizophrenia. Am J Med Genet. 2002, 114: 79-83. 10.1002/ajmg.10116.CrossRefPubMed

10.

Porton B, Ferreira A, DeLisi LE, Kao HT: A rare polymorphism affects a mitogen-activated protein kinase site in synapsin III: possible relationship to schizophrenia. Biol Psychiatry. 2004, 55: 118-125. 10.1016/j.biopsych.2003.07.002.CrossRefPubMed

11.

Lachman HM, Stopkova P, Rafael MA, Saito T: Association of schizophrenia in African Americans to polymorphism in synapsin III gene. Psychiatr Genet. 2005, 15: 127-132. 10.1097/00041444-200506000-00009.CrossRefPubMed

12.

Lachman HM, Stopkova P, Papolos DF, Pedrosa E, Margolis B, Aghalar MR, Saito T: Analysis of synapsin III-196 promoter mutation in schizophrenia and bipolar disorder. Neuropsychobiology. 2006, 53: 57-62. 10.1159/000091720.CrossRefPubMed

13.

Vawter MP, Thatcher L, Usen N, Hyde TM, Kleinman JE, Freed WJ: Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia. Mol Psychiatry. 2002, 7: 571-578. 10.1038/sj.mp.4001158.CrossRefPubMed

14.

Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P: Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron. 2000, 28: 53-67. 10.1016/S0896-6273(00)00085-4.CrossRefPubMed

15.

Halim ND, Weickert CS, McClintock BW, Hyde TM, Weinberger DR, Kleinman JE, Lipska BK: Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development. Mol Psychiatry. 2003, 8: 797-810. 10.1038/sj.mp.4001319.CrossRefPubMed

16.

Porton B, Wetsel WC: Reduction of synapsin III in the prefrontal cortex of individuals with schizophrenia. Schizophr Res. 2007, 94: 366-370. 10.1016/j.schres.2007.04.016.CrossRefPubMed

17.

Hallmayer J: The epidemiology of the genetic liability of schizophrenia. Aust NZ J Psyc. 2000, 34 (Suppl): S47-55. 10.1046/j.1440-1614.2000.00769.x.CrossRef

18.

Tienari PJ, Wynne LC: Adoption studies of schizophrenia. Ann Med. 1994, 26: 233-237. 10.3109/07853899409147896.CrossRefPubMed

19.

Cardno AG, Marshall EJ, Coid B, Macdonald AM, Ribchester TR, Davies NJ, Venturi P, Jones LA, Lewis SW, Sham PC, Gottesman II, Farmer AE, McGuffin P, Reveley AM, Murray RM: Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry. 1999, 56: 162-168. 10.1001/archpsyc.56.2.162.CrossRefPubMed

20.

Fischer M: Genetic and environmental factors in schizophrenia: a study of schizophrenic twins and their families. Acta Psychiatr Scand Suppl. 1973, 238: 9-142.PubMed

21.

Franzek E, Beckmann H: Different genetic background of schizophrenia spectrum psychosis: A twin study. Am J Psychiatry. 1998, 155 (1): 76-83.CrossRefPubMed

22.

Kringlen E, Cramer G: Offspring of Monozygotic twins discordant for schizophrenia. Arch Gen Psychiatry. 1989, 46: 873-877.CrossRefPubMed

23.

Sherman SL, DeFries JC, Gottesman II, Loehlin JC, Meyer JM, Pelias MZ, Rice J, Waldman I: Recent developments in human behavioural genetics: past accomplishments and future directions. Am J Hum Genet. 1997, 60: 1265-1275. 10.1086/515473.CrossRefPubMedPubMedCentral

24.

O'Reilly RL, Singh SM: Retroviruses and schizophrenia revisited. Am J Med Genet. 1996, 67: 19-24. 10.1002/(SICI)1096-8628(19960216)67:1<19::AID-AJMG3>3.0.CO;2-N.CrossRefPubMed

25.

Mednick SA, Machon RA, Huttunen MO, Bonett D: Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch. Gen Psych. 1988, 45: 189-192.CrossRef

26.

Karlsson H, Bachmann S, Schroder J, McArthur J, Torrey EF, Yolken RH: Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia. Proc Natl Acad Sci USA. 2001, 98: 4634-4639. 10.1073/pnas.061021998.CrossRefPubMedPubMedCentral

27.

Torrey EF, Miller J, Rawlings R, Yolken RH: Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophre Res. 1997, 28: 1-38. 10.1016/S0920-9964(97)00092-3.CrossRef

28.

Jablensky A: Epidemiology of schizophrenia: the global burden of disease and disability. Eur Arch Psych Clin Neurosci. 2000, 250: 274-285. 10.1007/s004060070002.CrossRef

29.

Pedersen CB, Mortensen PB: Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psych. 2001, 58: 1039-1046. 10.1001/archpsyc.58.11.1039.CrossRef

30.

Singh SM, Murphy B, O'Reilly R: Epigenetic contributors to the discordance of monozygotic twins. Clin Genet. 2002, 62: 97-103. 10.1034/j.1399-0004.2002.620201.x.CrossRefPubMed

31.

Singh SM, Murphy B, O'Reilly R: Monozygotic twins with chromosome 22q11 deletion and discordant phenotypes: updates with an epigenetic hypothesis. J Med Genet. 2002, 39: e71-10.1136/jmg.39.11.e71.CrossRefPubMedPubMedCentral

32.

Singh SM, Murphy BC, O'Reilly R: Involvement of gene-diet/drug interaction in DNA methylation and its contribution to complex diseases: from cancer to schizophrenia. Clin Genet. 2003, 64: 451-460. 10.1046/j.1399-0004.2003.00190.x.CrossRefPubMed

33.

Singh SM, McDonald P, Murphy BC, O'Reilly R: Incidental neurodevelopmental episodes in the etiology of schizophrenia: An expanded model involving epigenetics and development. Clin Genet. 2004, 65: 435-440. 10.1111/j.1399-0004.2004.00269.x.CrossRefPubMed

34.

Petronis A: The origin of schizophrenia: Genetic thesis, epigenetic antithesis, and resolving synthesis. Biol Psychiatry. 2001, 55: 965-970. 10.1016/j.biopsych.2004.02.005.CrossRef

35.

Murphy BC, O'Reilly RL, Singh SM: Site-specific methylation in S-COMT promoter in 31 brain regions with implications for studies involving schizophrenia. Am J Med Gen Part B (Neuropsychiatric Genet). 2005, 133B: 37-42. 10.1002/ajmg.b.30134.CrossRef

36.

Abdolmaleky HM, Cheng KH, Faraone SV, Wilcox M, Glatt SJ, Gao F, Smith CL, Shafa R, Aeali B, Carnevale J, Pan H, Papageorgis P, Ponte JF, Sivaraman V, Tsuang MT, Thiagalingam S: Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet. 2006, 15: 3132-3145. 10.1093/hmg/ddl253.CrossRefPubMedPubMedCentral

37.

Santos F, Dean W: Epigenetic reprogramming during early development in mammals. Reproduction. 2004, 127: 643-651. 10.1530/rep.1.00221.CrossRefPubMed

38.

Lehmann U, Brakensiek K, Kreipe H: Role of epigenetic changes in hematological malignancies. Ann Hematol. 2004, 83: 137-152. 10.1007/s00277-003-0798-7.CrossRefPubMed

39.

Pompeia C, Hodge DR, Plass C, Wu YZ, Marquex VE, Kelley JA, Farrar WL: Microarray analysis of epigenetic silencing of gene expression in the KAS-6/1 multiple myeloma cell line. Cancer Res. 2004, 64: 3465-3473. 10.1158/0008-5472.CAN-03-3970.CrossRefPubMed

40.

Iwamoto K, Bando M, Yamada K, Takao H, Iwayama-Shigano Y, Yoshikawa T, Kato T: DNA methylation status of SOX10 correlates with its down regulation and oligodendrocyte dysfunction in schizophrenia. J Neurosci. 2005, 25: 5376-81. 10.1523/JNEUROSCI.0766-05.2005.CrossRefPubMed

41.

Petronis A, Gottesman II, Kan P, Kennedy JL, Basile VS, Paterson AD, Popendikyte V: Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance?. Schizophr Bull. 2003, 29: 169-178.CrossRefPubMed

42.

Mills J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, Jia P, Assadzadeh A, Flanagan J, Schumacher A, Wang SC, Petronis A: Epigenomic profiling reveals DNA methylation changes associated with major psychosis. Am J Hum Genet. 2008, 82: 696-711. 10.1016/j.ajhg.2008.01.008.CrossRef

43.

Feinberg AP, Tycko B: The history of cancer epigenetics. Nat Rev Cancer. 2004, 4 (2): 143-153. 10.1038/nrc1279.CrossRefPubMed

44.

Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boiz-Chornet M, Sanchez-Qguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M: Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 2005, 102: 10604-10609. 10.1073/pnas.0500398102.CrossRefPubMedPubMedCentral

45.

Frommer M, McDonald LE, Millar DS, Collis CM, Watt F, Grigg GW, Molloy PL, Paul CL: A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci USA. 1992, 89: 1827-1831. 10.1073/pnas.89.5.1827.CrossRefPubMedPubMedCentral

46.

Feng J, Chi P, Blanpied TA, Xu Y, Magarinos AM, Ferreira A, Takahashi RH, Kao H, McEwen BS, Ryan TA, Augustine GJ, Greengard P: Regulation of neurotransmitter release by synapsin III. J Neurosci. 2002, 22: 4372-4380.PubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/9/115/prepub

Title: DNA methylation and mRNA expression of SYN III, a candidate gene for schizophrenia
Authors: Brenda C Murphy
Richard L O'Reilly
Shiva M Singh
Publication date: 01-12-2008
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2008
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/1471-2350-9-115

Keynote webinar | Spotlight on medication adherence

Springer Medicine

DNA methylation and mRNA expression of SYN III, a candidate gene for schizophrenia

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2008

Analysis of variants in DNA damage signalling genes in bladder cancer

A novel WFS1 mutation in a family with dominant low frequency sensorineural hearing loss with normal VEMP and EcochG findings

Association between variations in the TLR4gene and incident type 2 diabetes is modified by the ratio of total cholesterol to HDL-cholesterol

INSIG2 gene polymorphism is associated with increased subcutaneous fat in women and poor response to resistance training in men

Role of TGF-β1 haplotypes in the occurrence of myocardial infarction in young Italian patients

TCF7L2variant genotypes and type 2 diabetes risk in Brazil: significant association, but not a significant tool for risk stratification in the general population