Skip to main content

Endolymphatic hydrops and ionic transporters: genetic and biohumoral aspects

Abstract

Ménière’s disease (MD) is an inner ear disorder, characterized by a burden of symptoms, probably arising from the interplay of genetic and environmental factors. In this brief review, we consider the role of ion channels and transporters in the pathophysiology of MD, focusing on genetic and biohumoral aspects. Pathophysiological mechanisms related to altered concentrations of ions in the endolymph include altered osmotic pressure leading to hydrops and/or immunomodulatory effects of K+ and Endogenous Ouabain (EO) concentrations in the inner ear. Aquaporins 1–5 (AQPs) have been found in the inner ear; AQP2 is the only isoform controlled by a hormone, namely, vasopressin (antidiuretic hormone, ADH). Genetic studies on AQPs have provided inconclusive results. Recently, two genetic polymorphisms have been associated with MD: rs3746951, a missense variant (Gly180Ser) in the Salt-Inducible Kinase-1 (SIK1) gene and rs487119, an intronic variant of gene SLC8A1 coding for a Na+,Ca++ exchanger (NCX-1). EO is a hormone released by the midbrain and adrenal glands. It controls the constitutive capacity of modulating Na+,K+-ATPase activity. Higher plasma levels of EO have been found in MD subjects compared to a control group.

This is a preview of subscription content, access via your institution.

References

  1. Lopez-Escamez JA, Carey J, Chung WH, Goebel JA, Magnusson M, Mandalà M et al (2015) Diagnostic criteria for Ménière's disease. J Vestib Res 25:1–7. https://doi.org/10.3233/VES-150549

    Article  PubMed  Google Scholar 

  2. Requena T, Espinosa-Sanchez JM, Cabrera S, Trinidad G, Soto-Varela A, Santos-Perez S, Teggi R, Perez P, Batuecas-Caletrio A, Fraile J, Aran I, Martin E, Benitez J, Perez-Fernandez N, Lopez-Escamez JA (2014) Familial clustering and genetic heterogeneity in Meniere’s disease. Clin Genet 85(3):245–252. https://doi.org/10.1111/cge.12150

    Article  CAS  PubMed  Google Scholar 

  3. Morrison AW (1995) Anticipation in Meniere's disease. J Laryngol Otol 109:499–502. https://doi.org/10.1017/S0022215100130567

    Article  CAS  PubMed  Google Scholar 

  4. Frejo L, Giegling I, Teggi R, Lopez-Escamez JA, Rujescu D (2016) Genetics of vestibular disorders: pathophysiological insights. J Neurol 263(Suppl 1):45–53. https://doi.org/10.1007/s00415-015-7988-9

    Article  CAS  PubMed Central  Google Scholar 

  5. Lang F, Vallon V, Knipper M, Wangemann P (2007) Functional significance of channels and transporters expressed in the inner ear and kidney. Am J Physiol Cell Physiol 293:1187–1208. https://doi.org/10.1152/ajpcell.00024.2007

    Article  CAS  Google Scholar 

  6. Candreia C, Schmuziger N, Gurtler N (2010) Molecular analysis of aquaporin genes 1 to 4 in patients with Ménière’s Disease. Cell Physiol Biochem 26:787–792. https://doi.org/10.1159/000322346

    Article  CAS  PubMed  Google Scholar 

  7. Lopes de Carvalho K, Sartorato EL, da Silva-Costa SM, de Macedo Adamov NS, Ganança FF (2016) Ménière's disease: molecular analysis of aquaporins 2, 3 and potassium channel KCNE1 genes in Brazilian patients. Otol Neurotol 37:1117–1121. https://doi.org/10.1097/MAO.0000000000001136

    Article  Google Scholar 

  8. Mallur PS, Weisstuch A, Pfister M et al (2010) Aquaporin-2 and -4: single nucleotide polymorphisms in Ménière’s disease patients. Audiol Med 8:18–23. https://doi.org/10.1159/000322346

    Article  CAS  Google Scholar 

  9. Friedmann I, Fraser GR, Froggatt P (1966) Pathology of the ear in the cardioauditory syndrome of Jervell and Lange–Nielsen (recessive deafness with electrocardiographic abnormalities. J Laryngol Otol 80:451–470. https://doi.org/10.1017/s002221510006552x

    Article  CAS  PubMed  Google Scholar 

  10. Li YJ, Jin ZG, Xu XR (2016) Variants in the KCNE1 or KCNE3 gene and risk of Ménière's disease: a meta-analysis. J Vestib Res 25:211–218. https://doi.org/10.3233/VES-160569

    Article  CAS  PubMed  Google Scholar 

  11. Mori N, Miyashita T, Inamoto R, Matsubara A, Mori T, Akiyama K, Hoshikawa H (2017) Ion transport its regulation in the endolymphatic sac: suggestions for clinical aspects of Meniere's disease. Eur Arch Otolaryngol 274:1813–1820. https://doi.org/10.1007/s00405-016-4362-1

    Article  Google Scholar 

  12. Bartolami S, Gaboyard S, Quentin J, Travo C, Cavalier M, Barhanin J, Chabbert C (2011) Critical roles of transitional cells and Na/K-ATPase in the formation of vestibular endolymph. J Neurosci 31:16541–16549. https://doi.org/10.1523/JNEUROSCI.2430-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Alper SL, Sharma AK (2013) The SLC26 gene family of anion transporters and channels. Mol Aspects Med 34:494–515. https://doi.org/10.1016/j.mam.2012.07.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mittal R, Aranke M, Debs LH, Nguyen D, Patel AP, Grati M, Mittal J, Yan D, Chapagain P, Eshraghi AA, Liu XZ (2017) Indispensable role of ion channels and transporters in the auditory system. J Cell Physiol 232:743–758. https://doi.org/10.1002/jcp.25631

    Article  CAS  PubMed  Google Scholar 

  15. Wangemann P, Itza EM, Albrecht B, Wu T, Jabba SV, Maganti RJ, Marcus DC (2004) Loss of mKCNJ10 protein expression abolishes endocochlear potential and causes deafness in Pendred syndrome mouse model. BMC Med 2:30. https://doi.org/10.1186/1741-7015-2-30

    Article  PubMed  PubMed Central  Google Scholar 

  16. Usami S, Abe S, Weston MD, Shinkawa H, Van Camp G, Kimberling WJ (1999) Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations. Hum Genet 104:188–192. https://doi.org/10.1007/s004390050933

    Article  CAS  PubMed  Google Scholar 

  17. Xia AP, Kikuchi T, Minowa O et al (2002) Late-onset hearing loss in a mouse model of DFN3 non-syndromic deafness: morphologic and immunohistochemical analyses. Hear Res 166:150–158. https://doi.org/10.1016/S0378-5955(02)00309-X

    Article  PubMed  Google Scholar 

  18. Ciorba A, Corazzi V, Bianchini C, Aimoni C, Skarzynski H, Skarzynski PH, Hatzopoulos S (2016) Sudden sensorineural hearing loss: Is there a connection with inner ear electrolytic disorders? a literature review. Int J Immunopathol Pharmacol 29:595–602. https://doi.org/10.1177/0394632016673845

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ross MD, Ernst SA, Kerr TP (1982) Possible functional roles of Na+, K+-ATPase in the inner ear and their relevance to Ménière's disease. Am J Otolaryngol 3:353–360. https://doi.org/10.1016/S0196-0709(82)80010-0

    Article  CAS  PubMed  Google Scholar 

  20. Ferrandi M, Salardi S, Tripodi G et al (1999) Evidence for an interaction between adducing and Na(+)-K(+)YATPase: relation to genetic hypertension. Am J Physiol 277:1338–1349. https://doi.org/10.1152/ajpheart.1999.277.4.H1338

    Article  Google Scholar 

  21. Teggi R, Lanzani C, Zagato L, Delli Carpini S, Manunta P, Bianchi G, Bussi M (2008) Gly460Trp alpha-adducin mutation as a possible mechanism leading to endolymphatic hydrops in Ménière's syndrome. Otol Neurotol 29:824–828. https://doi.org/10.1097/MAO.0b013e318180a4b1

    Article  PubMed  Google Scholar 

  22. Teggi R, Zagato L, Delli Carpini S, Citterio L, Cassandro C, Albera R, Yang WY, Staessen JA, Bussi M, Manunta P, Lanzani C (2017) Genetics of ion homeostasis in Ménière's disease. Eur Arch Otorhinolaryngol 274:757–763. https://doi.org/10.1007/s00405-016-4375-9

    Article  PubMed  Google Scholar 

  23. Degerman E, Rauch U, Goransson O, Lindberg S, Hultgardh A, Magnusson M (2011) Identification of new signaling components in the sensory epithelium of human saccule. Front Neurol 2:e48. https://doi.org/10.3389/fneur.2011.00048

    Article  Google Scholar 

  24. Bouzinova EV, Hangaard L, Staehr C, Mazur A, Ferreira A, Chibalin AV, Sandow SL, Xie Z, Aalkjaer C, Matchkov VV (2018) The α2 isoform Na, K-ATPase modulates contraction of rat mesenteric small artery via cSrc-dependent Ca2+ sensitization. Acta Physiol (Oxf) 224:e13059. https://doi.org/10.1111/apha.13059

    Article  CAS  Google Scholar 

  25. Teggi R, Zagato L, Delli Carpini S, Messaggio E, Casamassima N, Lanzani C, Manunta P, Bussi M (2010) Endogenous ouabain in Ménière's disease. Otol Neurotol 31:153–156. https://doi.org/10.1097/MAO.0b013e3181c0eaba

    Article  PubMed  Google Scholar 

  26. Teggi R, Zagato L, Lanzani C et al (2018) J Vestib Res 28:44. https://doi.org/10.3233/VES-180635

    Article  Google Scholar 

  27. Degerman E, In 't Zandt R, Pålbrink AK, Magnusson M. (2015) Vasopressin induces endolymphatic hydrops in mouse inner ear, as evaluated with repeated 9.4 T MRI Hear Res. 330:119–124. https://doi.org/10.1016/j.heares.2015.05.008

    Article  CAS  PubMed  Google Scholar 

  28. Khalaf FK, Dube P, Mohamed A, Tian J, Malhotra D, Haller ST, Kennedy DJ (2018) Cardiotonic steroids and the sodium trade balance: new insights into trade-off mechanisms mediated by the Na+/K+-ATPase. Int J Mol Sci 30:e2576. https://doi.org/10.3390/ijms19092576

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Roberto Teggi.

Ethics declarations

Conflicts of interest

The author declares that they have no conflict of interest.

Additional information

This manuscript is part of a supplement sponsored by the German Federal Ministry of Education and Research within the funding initiative for integrated research and treatment centers.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Teggi, R., Carpini, S.D. & Zagato, L. Endolymphatic hydrops and ionic transporters: genetic and biohumoral aspects. J Neurol 266, 47–51 (2019). https://doi.org/10.1007/s00415-019-09399-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-019-09399-6

Keywords

  • Ménière’s disease
  • Hydrops
  • Ionic exchangers
  • Endogenous Ouabain
  • Aquaporins