Journal of Neural Transmission

, Volume 122, Issue 6, pp 819–823 | Cite as

Neuronal nitric oxide synthase (nNOS, NOS1) rs693534 and rs7977109 variants and risk for restless legs syndrome

  • Félix Javier Jiménez-Jiménez
  • Hortensia Alonso-Navarro
  • Carmen Martínez
  • Martín Zurdo
  • Laura Turpín-Fenoll
  • Jorge Millán-Pascual
  • Teresa Adeva-Bartolomé
  • Esther Cubo
  • Francisco Navacerrada
  • Ana Rojo-Sebastián
  • Lluisa Rubio
  • Marisol Calleja
  • José Francisco Plaza-Nieto
  • Belén Pilo-de-la-Fuente
  • Margarita Arroyo-Solera
  • Esteban García-Albea
  • Elena García-Martín
  • José A. G. Agúndez
Neurology and Preclinical Neurological Studies - Original Article

Abstract

Several biochemical, neuropathological, and experimental data suggest a possible role of nitric oxide (NO) in the pathophysiology of restless legs syndrome (RLS). Two single nucleotide polymorphisms (SNPs) neuronal nitric oxide synthase (nNOS or NOS1) gene (rs7977109 and rs693534) have been found to be associated with the risk for RLS in Germans, although only one of them (rs7977109) remained as significant after multiple comparison tests. The aim of our study was to replicate the possible association between these SNPs and risk for RLS in the Spanish population. We studied the allelic and genotype frequencies of the SNPs rs7977109 and rs693534 in 205 patients with RLS and 328 healthy controls using TaqMan genotyping. The rs7977109 and rs693534 genotypes and allelic frequencies did not significantly differ between patients with RLS and controls and were unrelated with the age at onset of RLS, gender, ferritin levels, and response to dopaminergic or gabaergic agents. The rs7999109GA genotype was overrepresented in RLS patients with positive family history of RLS, and in patients with symptomatic response to clonazepam. The results of our study suggest that these two NOS1 SNPs are not related to the overall risk for RLS in the Spanish population.

Keywords

Restless legs syndrome Genetics NOS1 gene Polymorphisms Risk factors Nitric oxide Oxidative stress 

Notes

Acknowledgments

Financed by Grants PI12/00241, PI12/00324, and RETICS RD12/0013/0002 (Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Madrid, Spain); GR10068 (Junta de Extremadura, Mérida, Spain), and PRIS10016 (Fundesalud, Mérida, Spain). Partially financed with FEDER funds.

Conflict of interest

None of the authors reported conflicts of interest.

Supplementary material

702_2014_1322_MOESM1_ESM.doc (102 kb)
Supplementary material 1 (DOC 102 kb)

References

  1. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir J (2003) Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology: a report from the restless legs syndrome diagnosis and epidemiology work shop at the National Institute of Health. Sleep Med 4:101–119CrossRefPubMedGoogle Scholar
  2. Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelmann JW, Zucconi M, Ferri R, Trenkwalder C, Lee HB, International Restless Legs Syndrome Study Group (2014) Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated international restless legs syndrome study group (IRLSSG) consensus criteria—history, rationale, description, and significance. Sleep Med 15:860–873CrossRefPubMedGoogle Scholar
  3. Baskol G, Korkmaz S, Erdem F, Caniklioglu A, Kocyigit M, Aksu M (2012) Assessment of nitric oxide, advanced oxidation protein products, malondialdehyde, and thiol levels in patients with restless legs syndrome. Sleep Med 13:414–418CrossRefPubMedGoogle Scholar
  4. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Statist Soc Ser B 1:289–300Google Scholar
  5. Clemens S, Sawchuk MA, Hochman S (2005) Reversal of the circadian expression of tyrosine-hydroxylase but not nitric oxide synthase levels in the spinal cord of dopamine D3 receptor knockout mice. Neuroscience 133:353–357CrossRefPubMedCentralPubMedGoogle Scholar
  6. Ekbom KA (1945) Restless legs. Acta Med Suppl 158:5–123Google Scholar
  7. Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG (2013a) Latest perspectives in genetic risk factors for restless legs syndrome. Eur Neurol Rev 8:90–96Google Scholar
  8. Jiménez-Jiménez FJ, Alonso-Navarro H, Martínez C, Zurdo M, Turpín-Fenoll L, Millán J, Adeva-Bartolomé T, Cubo E, Navacerrada F, Rojo-Sebastián A, Rubio L, Calleja M, Plaza-Nieto JF, Pilo-de-la-Fuente B, Arroyo-Solera M, Agúndez JAG, García-Martín E (2013b) Dopamine receptor D3 (DRD3) gene rs6280 variant and risk for restless legs syndrome. Sleep Med 14:382–384CrossRefPubMedGoogle Scholar
  9. Jiménez-Jiménez FJ, Alonso-Navarro H, Martínez C, Zurdo M, Turpín-Fenoll L, Millán-Pascual J, Adeva-Bartolomé T, Cubo E, Navacerrada F, Rojo-Sebastián A, Rubio L, Calleja M, Plaza-Nieto JF, Pilo-de-la-Fuente B, Arroyo-Solera M, García-Martín E, Agúndez JAG (2014) The solute carrier family 1 (glial high affinity glutamate transporter), member 2 gene, SLC1A2, rs3794087 variant and assessment risk for restless legs syndrome. Sleep Med 15:266–268CrossRefPubMedGoogle Scholar
  10. Kiss JP, Hennings EC, Zsilla G, Vizi ES (1999) A possible role of nitric oxide in the regulation of dopamine transporter function in the striatum. Neurochem Int 34:345–350CrossRefPubMedGoogle Scholar
  11. Liu Y (1996) Nitric oxide influences dopaminergic processes. Adv Neuroimmunol 6:259–264CrossRefPubMedGoogle Scholar
  12. Molina JA, Jiménez-Jiménez FJ, Ortí-Pareja M, Navarro JA (1998) The role of nitric oxide in neurodegeneration: potential for pharmacological intervention. Drugs Aging 12:251–259CrossRefPubMedGoogle Scholar
  13. Patton SM, Ponnuru P, Snyder AM, Podskalny GD, Connor JR (2011) Hypoxia-inducible factor pathway activation in restless legs syndrome patients. Eur J Neurol 18:1329–1335CrossRefPubMedGoogle Scholar
  14. Roco A, Jiménez-Jiménez FJ, Alonso-Navarro H, Martínez C, Zurdo M, Turpín-Fenoll L, Millán J, Adeva-Bartolomé T, Cubo E, Navacerrada F, Rojo-Sebastián A, Rubio L, Calleja M, Plaza-Nieto JF, Pilo-de-la-Fuente B, Arroyo-Solera M, García-Martín E, Agúndez JA (2013) MAPT1 gene rs1052553 variant is unrelated with the risk for restless legs syndrome. J Neural Transm 120:463–467CrossRefPubMedGoogle Scholar
  15. Segovia G, Mora F (1998) Role of nitric oxide in modulating the release of dopamine, glutamate, and GABA in striatum of the freely moving rat. Brain Res Bull 45:275–279CrossRefPubMedGoogle Scholar
  16. Ulfberg J (2012) Treatment of restless legs syndrome with a nitroglycerin patch. Sleep Med 13:1326CrossRefPubMedGoogle Scholar
  17. West AR, Galloway MP (1997) Endogenous nitric oxide facilitates striatal dopamine and glutamate efflux in vivo: role of ionotropic glutamate receptor-dependent mechanisms. Neuropharmacology 36:1571–1581CrossRefPubMedGoogle Scholar
  18. Winkelmann J, Lichtner P, Schormair B, Uhr M, Hauk S, Stiasny-Kolster K, Trenkwalder C, Paulus W, Peglau I, Eisensehr I, Illig T, Wichmann HE, Pfister H, Golic J, Bettecken T, Pütz B, Holsboer F, Meitinger T, Müller-Myhsok B (2008) Variants in the neuronal nitric oxide synthase (nNOS, NOS1) gene are associated with restless legs syndrome. Mov Disord 23:350–358CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Félix Javier Jiménez-Jiménez
    • 1
    • 2
  • Hortensia Alonso-Navarro
    • 1
    • 2
  • Carmen Martínez
    • 3
  • Martín Zurdo
    • 4
  • Laura Turpín-Fenoll
    • 5
  • Jorge Millán-Pascual
    • 5
  • Teresa Adeva-Bartolomé
    • 6
  • Esther Cubo
    • 7
  • Francisco Navacerrada
    • 1
  • Ana Rojo-Sebastián
    • 2
  • Lluisa Rubio
    • 2
  • Marisol Calleja
    • 1
  • José Francisco Plaza-Nieto
    • 1
  • Belén Pilo-de-la-Fuente
    • 1
  • Margarita Arroyo-Solera
    • 1
  • Esteban García-Albea
    • 2
  • Elena García-Martín
    • 8
  • José A. G. Agúndez
    • 9
  1. 1.Section of NeurologyHospital Universitario del SuresteArganda del Rey, MadridSpain
  2. 2.Department of Medicine-NeurologyHospital “Príncipe de Asturias”. Universidad de AlcaláMadridSpain
  3. 3.Department of PharmacologyUniversity of ExtremaduraBadajozSpain
  4. 4.Section of NeurologyHospital Virgen del PuertoPlasenciaSpain
  5. 5.Section of NeurologyHospital La Mancha-CentroAlcázar De San JuanSpain
  6. 6.Unit of NeurologyClínica RecoletasZamoraSpain
  7. 7.Section of NeurologyHospital Universitario de BurgosBurgosSpain
  8. 8.Department of Biochemistry and Molecular BiologyUniversidad de ExtremaduraCáceresSpain
  9. 9.Department of PharmacologyUniversity of ExtremaduraCáceresSpain

Personalised recommendations