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01-05-2019 | Juvenile Myoclonic Epilepsy | Original Article

Methylation of cation–chloride cotransporters NKCC1 and KCC2 in patients with juvenile myoclonic epilepsy

Authors: Fatma Genç, Murat Kara, Yasemin Ünal, Elif Uygur Küçükseymen, Yasemin Biçer Gömceli, Taner Kaynar, Kürşad Tosun, Gülnihal Kutlu

Published in: Neurological Sciences | Issue 5/2019

Abstract

The etiology of juvenile myoclonic epilepsy (JME) is still unknown and the process of elaboration of multiple genetic mechanisms is ongoing. The aim of this study was to investigate the potential role of NKCC1 (SCL12A2) and KCC2 (SCL12A5) in JME by comparing their DNA methylation status in patients with JME versus healthy controls. Forty-nine patients with JME and 39 healthy individuals were compared for DNA methylation at the 5CpG islands. A total of 71 (81%) samples were found to have methylation in the NKCC1 gene, 36 (73%) from patients and 35 (90%) from healthy individuals. Out of the KCC2 samples, 50 (57%) were found to have methylation, 33 (67%) from patients and 17 (44%) from healthy individuals. In patients with JME, methylation of NKCC1 (73%) was lower than its methylation in the controls (90%) (p = 0.047). On the other hand, methylation of KCC2 in patients with JME (67%) was greater than the methylation in the controls (44%) (p = 0.022). Twenty-eight patients were treated with VPA and ongoing medications were not found to be associated with methylation (p > 0.05). In the present study, we determined significantly lower NKCC1 DNA methylation and significantly higher KCC2 DNA methylation levels in patients with JME compared with the healthy controls. This implies that NKCC1 expression can be higher and KCC2 expression can be reduced in affected people. Further studies that investigate the potential effect of DNA methylation mechanisms regulating gene expression on seizure activity and how they change JME network activity will be helpful.

Camfield CS, Striano P, Camfield PR (2013) Epidemiology of juvenile myoclonic epilepsy. Epilepsy Behav 28(Suppl 1):S15–S17. https://doi.org/10.1016/j.yebeh.2012.06.024 CrossRefPubMed

Dedei Daryan M, Güveli BT, Baslo SA, Mulhan K, Sarı H, Balçık ZE, Ataklı D (2018) Prevalence and clinical characteristics of headache in juvenile myoclonic epilepsy: experience from a tertiary epilepsy center. Neurol Sci 39(3):519–525. https://doi.org/10.1007/s10072-017-3232-y CrossRefPubMed

Baykan B, Wolf P (2017) Juvenile myoclonic epilepsy as a spectrum disorder: a focused review. Seizure 49:36–41. https://doi.org/10.1016/j.seizure.2017.05.011 CrossRefPubMed

Desai D, Desai S, Jani T (2016) Juvenile myoclonic epilepsy in rural Western India: not yet a benign syndrome. Epilepsy Res Treat 2016:1435150. https://doi.org/10.1155/2016/1435150 CrossRefPubMedPubMedCentral

Kobow K, Blümcke I (2018) Epigenetics in epilepsy. Neurosci Lett 667:40–46. https://doi.org/10.1016/j.neulet.2017.01.012

International League Against Epilepsy Consortium on Complex Epilepsies (2018) Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun 9(1):5269. https://doi.org/10.1038/s41467-018-07524-z CrossRef

Younus I, Reddy DS (2017) Epigenetic interventions for epileptogenesis: a new frontier for curing epilepsy. Pharmacol Ther 177:108–122. https://doi.org/10.1016/j.pharmthera.2017.03.002 CrossRefPubMedPubMedCentral

Li XQ, Guo YY, De W et al (2012) DNA methylation and microRNAs in cancer. World J Gastroenterol 18(9):882–888. https://doi.org/10.3748/wjg.v18.i9.882 CrossRefPubMedPubMedCentral

Pathak S, Miller J, Morris EC, Stewart WCL, Greenberg DA (2018) DNA methylation of the BRD2 promoter is associated with juvenile myoclonic epilepsy in Caucasians. Epilepsia 59(5):1011–1019. https://doi.org/10.1111/epi.14058 CrossRefPubMedPubMedCentral

10.

Hirose C (2014) Mutant GABAA receptor subunits in genetic (idiopathic) epilepsy. Prog Brain Res 213:55–85. https://doi.org/10.1016/B978-0-444-63326-2.00003-X CrossRefPubMed

11.

Watanabe M, Fukuda A (2015) Development and regulation of chloride homeostasis in the central nervous system. Front Cell Neurosci 9:371. https://doi.org/10.3389/fncel.2015.00371 CrossRefPubMedPubMedCentral

12.

Craiu D (2013) What is special about the adolescent (JME) brain? Epilepsy Behav 28(Suppl 1):S45–S51. https://doi.org/10.1016/j.yebeh.2012.12.008 CrossRefPubMed

13.

Hattingen E, Lückerath C, Pellikan S, Vronski D, Roth C (2014) Frontal and thalamic changes of GABA concentration indicate dysfunction of thalamofrontal networks in juvenile myoclonic epilepsy. Epilepsia 55(7):1030–1037. https://doi.org/10.1111/epi.12656 CrossRefPubMed

14.

González MI (2016) Regulation of the cell surface expression of chloride transporters during epileptogenesis. Neurosci Lett 628:213–218. https://doi.org/10.1016/j.neulet.2016.06.042 CrossRefPubMedPubMedCentral

15.

Kasteleijn-Nolst Trenité DG, Schmitz B, Janz D, Delgado-Escueta AV, Thomas P et al (2013) Consensus on diagnosis and management of JME: From founder’s observations to current trends. Epilepsy Behav 28(Suppl 1):S87–S90. https://doi.org/10.1016/j.yebeh.2012.11.051 CrossRefPubMed

16.

Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW, Moshé SL, Nordli D, Plouin P, Scheffer IE (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology. 2005–2009. Epilepsia 51(4):676–685. https://doi.org/10.1111/j.1528-1167.2010.02522.x CrossRefPubMed

17.

Dalton SR, Bellacosa A (2012) DNA demethylation by TDG. Epigenomics 4(4):459–467. https://doi.org/10.2217/epi.12.36 CrossRefPubMed

18.

Song J, Teplova M, Ishibe-Murakami S, Patel DJ (2012) Structure-based mechanistic insights into DNMT1-mediated maintenance DNA methylation. Science 335:709–712. https://doi.org/10.1126/science.1214453 CrossRefPubMedPubMedCentral

19.

Szyf M, Knox DJ, Milutinovic S, Slack AD, Araujo FD (2000) How does DNA methyltransferase cause oncogenic transformation? Ann N Y Acad Sci 910:156–174CrossRefPubMed

20.

Zhu L, Polley N, Mathews GC, Delpire E (2008) NKCC1 and KCC2 prevent hyperexcitability in the mouse hippocampus. Epilepsy Res 79(2–3):201–212. https://doi.org/10.1016/j.eplepsyres.2008.02.005 CrossRefPubMedPubMedCentral

21.

Taskıran E, Bebek N (2015) Drug resistance and resistance mechanisms in epilepsy. Epilepsi 21(2):43–53. https://doi.org/10.5505/epilepsi.2015.50570

22.

Blaesse P, Airaksinen MS, Rivera C, Kaila K (2009) Cation-chloride cotranspoters and neuronal function. Neuron 61:820–838. https://doi.org/10.1016/j.neuron.2009.03.003 CrossRefPubMed

23.

Li X, Zhou J, Chen Z, Chen S, Zhu F (2008) Long-term expressional changes of Na+ -K+ -Cl- co-transporter 1 (NKCC1) and K+ -Cl- co-transporter 2 (KCC2) in CA1 region of hippocampus following lithium-pilocarpine induced status epilepticus (PISE). Brain Res 1221:141–146. https://doi.org/10.1016/j.brainres.2008.04.047 CrossRefPubMed

24.

Palma E, Amici M, Sobrero F, Spinelli G, Di Angelantonio S (2006) Anomalous levels of Cl- transporters in the hippocampal subiculum from temporal lobe epilepsy patients make GABA excitatory. Proc Natl Acad Sci U S A 103(22):8465–8468. https://doi.org/10.1073/pnas.0602979103 CrossRefPubMedPubMedCentral

25.

Gómez-Lira G, Mendoza-Torreblanca JG, Granados-Rojas L (2011) Ketogenic diet does not change NKCC1 and KCC2 expression in rat hippocampus. Epilepsy Res 96(1–2):166–171. https://doi.org/10.1016/j.eplepsyres.2011.05.017 CrossRefPubMed

26.

Lösher W, Puskarjov M, Kaila K (2013) Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology 69:62–74. https://doi.org/10.1016/j.neuropharm.2012.05.045

27.

Jakovcevski M, Akbarian S (2012) Epigenetic mechanisms in neurological disease. Nat Med 18:1194–1204. https://doi.org/10.1038/nm.2828 CrossRefPubMedPubMedCentral

28.

Belhedi N, Perroud N, Karege F, Vessaz M, Malafosse A, Salzmann A (2014) Increased CPA6 promoter methylation in focal epilepsy and in febrile seizures. Epilepsy Res 108:144–148. https://doi.org/10.1016/j.eplepsyres.2013.10.007

29.

Illingworth R, Kerr A, Desousa D et al (2008) A novel CpG island set identifies tissue-specific methylation at developmental gene loci. PLoS Biol 6(1):e22. https://doi.org/10.1371/journal.pbio.0060022

Title: Methylation of cation–chloride cotransporters NKCC1 and KCC2 in patients with juvenile myoclonic epilepsy
Authors: Fatma Genç
Murat Kara
Yasemin Ünal
Elif Uygur Küçükseymen
Yasemin Biçer Gömceli
Taner Kaynar
Kürşad Tosun
Gülnihal Kutlu
Publication date: 01-05-2019
Publisher: Springer International Publishing
Keywords: Juvenile Myoclonic Epilepsy
Epilepsy
Valproate
Epigenetics
Published in: Neurological Sciences / Issue 5/2019
Print ISSN: 1590-1874
Electronic ISSN: 1590-3478
DOI: https://doi.org/10.1007/s10072-019-03743-4

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Springer Medicine

Methylation of cation–chloride cotransporters NKCC1 and KCC2 in patients with juvenile myoclonic epilepsy

Abstract

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Springer Medicine

Abstract

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