Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Research Article
  • Published:

Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia

Molecular Psychiatry volume 8, pages 524–535 (2003)Cite this article

Abstract

The small-conductance calcium-activated K+ channel SK3 (SKCa3/KCNN3) regulates electrical excitability and neurotransmitter release in monoaminergic neurons, and has been implicated in schizophrenia, ataxia and anorexia nervosa. We have identified a novel SK3 transcript, SK3-1B that utilizes an alternative first exon (exon 1B), but is otherwise identical to SK3. SK3-1B, mRNA is widely distributed in human tissues and is present at 20–60% of SK3 in the brain. The SK3-1B protein lacks the N-terminus and first transmembrane segment, and begins eight residues upstream of the second transmembrane segment. When expressed alone, SK3-1B did not produce functional channels, but selectively suppressed endogenous SK3 currents in the pheochromocytoma cell line, PC12, in a dominant-negative fashion. This dominant inhibitory effect extended to other members of the SK subfamily, but not to voltage-gated K+ channels, and appears to be due to intracellular trapping of endogenous SK channels. The effect of SK3-1B expression is very similar to that produced by expression of the rare SK3 truncation allele, SK3-Δ, found in a patient with schizophrenia. Regulation of SK3 and SK3-1B levels may provide a potent mechanism to titrate neuronal firing rates and neurotransmitter release in monoaminergic neurons, and alterations in the relative abundance of these proteins could contribute to abnormal neuronal excitability, and to the pathogenesis of schizophrenia.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Storm JF . Potassium currents in hippocampal pyramidal cells. Prog Brain Res 1990; 83: 161–187.

    Article  CAS  PubMed  Google Scholar 

  2. Sah P . Ca2+-activated K+ currents in neurones: types, physiological roles and modulation. Trends Neurosci 1996; 19: 150–154.

    Article  CAS  PubMed  Google Scholar 

  3. Ishii TM, Maylie J, Adelman JP . Determinants of apamin and d-tubocurarine block in SK potassium channels. J Biol Chem 1997; 272: 23195–23200.

    Article  CAS  PubMed  Google Scholar 

  4. Koronyo-Hamaoui M, Danziger Y, Frisch A, Stein D, Leor S, Laufer N et al. Association between anorexia nervosa and the hsKCa3 gene: a family-based and case control study. Mol Psychiatry 2002; 7: 82–85.

    Article  CAS  PubMed  Google Scholar 

  5. Figueroa KP, Chan P, Schols L, Tanner C, Riess O, Perlman SL et al. Association of moderate polyglutamine tract expansions in the slow calcium-activated potassium channel type 3 with ataxia. Arch Neurol 2001; 58: 1649–1653.

    Article  CAS  PubMed  Google Scholar 

  6. Dror V, Shamir E, Ghanshani S, Kimhi R, Swartz M, Barak Y et al. hKCa3/KCNN3 potassium channel gene: association of longer CAG repeats with schizophrenia in Israeli Ashkenazi Jews, expression in human tissues and localization to chromosome 1q21. Mol Psychiatry 1999; 4: 254–260.

    Article  CAS  PubMed  Google Scholar 

  7. Brzustowicz LM, Hodgkinson KA, Chow EW, Honer WG, Bassett AS . Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21–q22. Science 2000; 288: 678–682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T, Martin R et al. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet 2001; 10: 1611–1617.

    Article  CAS  PubMed  Google Scholar 

  9. Gurling HMD, Kalsi G, Brynjohlfson J, Sigmundsson T, Sherrington R, Mankoo BS et al. Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21-22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3–24 and 20q12.1–11.23. Am J Hum Genet 2001; 68 661–673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ducros A, Joutel A, Vahedi K, Cecillon M, Ferreira A, Bernard E et al. Mapping of a second locus for familial hemiplegic migraine to 1q21–q23 and evidence of further heterogeneity. Ann Neurol 1997; 42: 885–890.

    Article  CAS  PubMed  Google Scholar 

  11. Cevoli S, Pierangeli G, Monari L, Valentino ML, Bernardoni P, Mochi M et al. Familial hemiplegic migraine: clinical features and probable linkage to chromosome 1 in an Italian family. Neurol Sci 2002; 23: 7–10.

    Article  CAS  PubMed  Google Scholar 

  12. Farde L . Brain imaging of schizophrenia—the dopamine hypothesis. Schizophr Res 1997; 28: 157–162.

    Article  CAS  PubMed  Google Scholar 

  13. Csernansky JG, Csernansky CA, Kogelman L, Montgomery EM, Bardgett ME . Progressive neurodegeneration after intracerebroventricular kainic acid administration in rats: Implications for schizophrenia? Biol Psychiatry 1998; 44: 1143–1150.

    Article  CAS  PubMed  Google Scholar 

  14. Laruelle M, Abi-Dargham P . Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies. J Psychopharmacol 1999; 13: 358–371.

    Article  CAS  PubMed  Google Scholar 

  15. Heckers S . Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus 2001; 11: 520–528.

    Article  CAS  PubMed  Google Scholar 

  16. Nopoulos PC, Ceilley JW, Gailis EA, Andreasen NC . An MRI study of midbrain morphology in patients with schizophrenia: relationship to psychosis, neuroleptics, and cerebellar neural circuitry. Biol Psychiatry 2001; 49: 13–19.

    Article  CAS  PubMed  Google Scholar 

  17. Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M et al. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 2002; 5: 267–271.

    Article  CAS  PubMed  Google Scholar 

  18. Stocker M, Pedarzani P . Differential distribution of three Ca2+-activated K+ channel subunits, SK1, SK2, and SK3, in the adult rat central nervous system. Mol Cell Neurosci 2000; 15: 476–493.

    Article  CAS  PubMed  Google Scholar 

  19. Rimini R, Rimland JM, Terstappen GC . Quantitative expression analysis of the small conductance calcium-activated potassium channels, SK1, SK2 and SK3, in human brain. Brain Res 2000; 85: 218–220.

    CAS  Google Scholar 

  20. Wolfart J, Neuhoff H, Franz O, Roeper J . Differential expression of the small-conductance, calcium-activated potassium channel SK3 is critical for pacemaker control in dopaminergic midbrain neurons. J Neurosci 2001; 21: 3443–3456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Stocker M, Krause M, Pedarzani P . An apamin-sensitive Ca2+-activated K+ current in hippocampal pyramidal neurons. Proc Natl Acad Sci USA 1999; 96: 4662–4667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Savic N, Pedarzani P, Sciancalepore M . Medium afterhyperpolarization and firing pattern modulation in interneurons of stratum radiatum in the CA3 hippocampal region. J Neurophysiol 2001; 85: 1986–1997.

    Article  CAS  PubMed  Google Scholar 

  23. Pedarzani P, Mosbacher J, Rivard A, Cingolani LA, Oliver D, Stocker M et al. Control of electrical activity in central neurons by modulating the gating of small conductance Ca2+-activated K+ channels. J Biol Chem 2001; 276: 9762–9769.

    Article  CAS  PubMed  Google Scholar 

  24. Steketee JD, Kalivas PW . Effect of microinjections of apamin into the A10-dopamine region of rats—a behavioral and neurochemical analysis. J Pharmacol Exp Ther 1990; 254: 711–719.

    CAS  PubMed  Google Scholar 

  25. Shepard PD, Bunney BS . Effects of apamin on the discharge properties of putative dopamine-containing neurons in vitro. Brain Res 1988; 463: 380–384.

    Article  CAS  PubMed  Google Scholar 

  26. Ping HX, Shepard PD . Apamin-sensitive Ca2+-activated K+ channels regulate pacemaker activity in nigral dopamine neurons. Neuroreport 1996; 7: 809–814.

    Article  CAS  PubMed  Google Scholar 

  27. Chandy KG, Fantino E, Wittekindt O, Kalman K, Tong LL, Ho TH et al. Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder? Mol Psychiatry 1998; 3: 32–37.

    Article  CAS  PubMed  Google Scholar 

  28. Bowen T, Guy CA, Craddock N, Cardno AG, Williams NM, Spurlock G et al. Further support for an association between a polymorphic CAG repeat in the hKCa3 gene and schizophrenia. Mol Psychiatry 1998; 3: 266–269.

    Article  CAS  PubMed  Google Scholar 

  29. Wittekindt O, Jauch A, Burgert E, Scharer L, Holtgreve-Grez H, Yvert G et al. The human small conductance calcium-regulated potassium channel gene (hSKCa3) contains two CAG repeats in exon 1, is on chromosome 1q21.3, and shows a possible association with schizophrenia. Neurogenetics 1998; 1: 259–265.

    Article  CAS  PubMed  Google Scholar 

  30. Cardno AG, Bowen T, Guy CA, Jones LA, McCarthy G, Williams NM et al. CAG repeat length in the hKCa3 gene and symptom dimensions in schizophrenia. Biol Psychiatry 1999; 45: 1592–1596.

    Article  CAS  PubMed  Google Scholar 

  31. O'Donovan MC, Owen MJ . Candidate-gene association studies of schizophrenia. Am J Hum Genet 1999; 65: 587–592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ritsner M, Modai I, Amir S, Halperin T, Weizman A et al. An association of CAG repeats at the KCNN3 locus with symptom dimensions of schizophrenia. Biol Psychiatry 2002; 51: 788–794.

    Article  CAS  PubMed  Google Scholar 

  33. Antonarakis SE, Blouin JL, Lasseter VK, Gehrig C, Radhakrishna U, Nestadt G et al. Lack of linkage or association between schizophrenia and the polymorphic trinucleotide repeat within the KCNN3 gene on chromosome 1q21. Am J Med Genet 1999; 88: 348–351.

    Article  CAS  PubMed  Google Scholar 

  34. Joober R, Benkelfat C, Brisebois K, Toulouse A, Lafreniere RG, Turecki G et al. Lack of association between the hSKCa3 channel gene CAG polymorphism and schizophrenia. Am J Med Genet 1999; 88: 154–157.

    Article  CAS  PubMed  Google Scholar 

  35. Bonnet-Brilhault F, Laurent C, Campion D, Thibaut F, Lafargue C, Charbonnier F et al. No evidence for involvement of KCNN3 (hSKCa3) potassium channel gene in familial and isolated cases of schizophrenia. Eur J Hum Genet 1999; 7: 247–250.

    Article  CAS  PubMed  Google Scholar 

  36. Hawi Z, Mynett-Johnson L, Murphy V, Straub RE, Kendler KS, Walsh D et al. No evidence to support the association of the potassium channel gene hSKCa3 CAG repeat with schizophrenia or bipolar disorder in the Irish population. Mol Psychiatry 1999; 4: 488–491.

    Article  CAS  PubMed  Google Scholar 

  37. Tsai MT, Shaw CK, Hsiao KJ, Chen CH . Genetic association study of a polymorphic CAG repeats array of calcium-activated potassium channel (KCNN3) gene and schizophrenia among the Chinese population from Taiwan. Mol Psychiatry 1999; 4: 271–273.

    Article  CAS  PubMed  Google Scholar 

  38. Chowdari KV, Wood J, Ganguli R, Gottesman II, Nimgaonkar VL . Lack of association between schizophrenia and a CAG repeat polymorphism of the hSKCa3 gene in a north eastern US sample. Mol Psychiatry 2000; 5: 237–238.

    Article  CAS  PubMed  Google Scholar 

  39. Stober G, Meyer J, Nanda I, Wienker TF, Saar K, Jatzke S et al. hKCNN3 which maps to chromosome 1q21 is not the causative gene in periodic catatonia, a familial subtype of schizophrenia. Eur Arch Psychiatry Clin Neurosci 2000; 250: 163–168.

    Article  CAS  PubMed  Google Scholar 

  40. Ujike H, Yamamoto A, Tanaka Y, Takehisa Y, Takaki M, Taked T et al. Association study of CAG repeats in the KCNN3 gene in Japanese patients with schizophrenia, schizoaffective disorder and bipolar disorder. Psychiatry Res 2001; 101: 203–207.

    Article  CAS  PubMed  Google Scholar 

  41. Bowen T, Williams N, Norton N, Spurlock G, Wittekindt OH, Morris-Rosendahl DJ et al. Mutation screening of the KCNN3 gene reveals a rare frameshift mutation. Mol Psychiatry 2001; 6: 259–260.

    Article  CAS  PubMed  Google Scholar 

  42. Miller MJ, Rauer H, Tomita H, Rauer H, Gargus JJ, Gutman GA et al. Nuclear localization and dominant-negative suppression by a mutant SKCa3 N-terminal channel fragment identified in a patient with schizophrenia. J Biol Chem 2001; 276: 27753–27756.

    Article  CAS  PubMed  Google Scholar 

  43. Dawson LA, Routledge C . Differential effects of potassium channel blockers on extracellular concentrations of dopamine and 5-HT in the striatum of conscious rats. Br J Pharmacol 1995; 116: 3260–3264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bardien-Kruger S, Wulff H, Arieff Z, Brink P, Chandy KG, Corfield V . Characterisation of the human voltage-gated potassium channel gene, KCNA7, a candidate gene for inherited cardiac disorders, and its exclusion as cause of progressive familial heart block I (PFHBI). Eur J Hum Genet 2002; 10: 36–43.

    Article  CAS  PubMed  Google Scholar 

  45. Tu L, Santarelli V, Sheng Z, Skach W, Pain D, Deutsch C . Voltage-gated K+ channels contain multiple intersubunit association sites. J Biol Chem 1996; 271: 18904–18911.

    Article  CAS  PubMed  Google Scholar 

  46. Joiner WJ, Khanna R, Schlichter LC, Kaczmarek LK . Calmodulin regulates assembly and trafficking of SK4/IK1 Ca2+-activated K+ channels. J Biol Chem 2001; 276: 37980–37985.

    CAS  PubMed  Google Scholar 

  47. Fanger CM, Rauer H, Neben AL, Miller MJ, Rauer H, Wulff H et al. Calcium-activated potassium channels sustain calcium signaling in T lymphocytes. J Biol Chem 2001; 276: 12249–12256.

    Article  CAS  PubMed  Google Scholar 

  48. Deutsch C . Potassium channel ontogeny. Annu Rev Physiol 2002; 64: 19–46.

    Article  CAS  PubMed  Google Scholar 

  49. Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 1998;280: 69–77.

    Article  CAS  PubMed  Google Scholar 

  50. Jiang YX, Lee A, Chen JY, Cadene M, Chait BT, MacKinnon R . The open pore conformation of potassium channels. Nature 2002; 417: 523–526.

    Article  CAS  PubMed  Google Scholar 

  51. Schumacher MA, Rivard AF, Bachinger HP, Adelman JP . Structure of the gating domain of a Ca2+-activated K+ channel complexed with Ca2+/calmodulin. Nature 2001; 410: 1120–1124.

    Article  CAS  PubMed  Google Scholar 

  52. Jiang YX, Lee A, Chen JY, Cadene M, Chait BT, MacKinnon R . Crystal structure and mechanism of a calcium-gated potassium channel. Nature 2002; 417: 515–522.

    Article  CAS  PubMed  Google Scholar 

  53. Sun G, Tomita H, Shakkottai VG, Gargus JJ . Genomic organization and promoter analysis of human KCNN3 gene. J Hum Genet 2001; 46: 463–470.

    Article  CAS  PubMed  Google Scholar 

  54. Wulff H, Gutman GA, Cahalan MD, Chandy KG . Delineation of the clotrimazole/TRAM-34 binding site on the intermediate conductance calcium-activated potassium channel, IKCa1. J Biol Chem 2001; 276: 32040–32045.

    Article  CAS  PubMed  Google Scholar 

  55. Shakkottai VG, Regaya I, Wulff H, Fajloun Z, Tomita H, Fathallah M et al. Design and characterization of a highly selective peptide inhibitor of the small conductance calcium-activated K+ channel, SkCa2. J Biol Chem 2001; 276: 43145–43151.

    Article  CAS  PubMed  Google Scholar 

  56. Grissmer S, Lewis RS, Cahalan MD . Ca2+-activated K+ channels in human leukemic T cells. J Gen Physiol 1992; 99: 63–84.

    Article  CAS  PubMed  Google Scholar 

  57. Desai R, Peretz A, Idelson H, Lazarovici P, Attali B . Ca2+-activated K+ channels in human leukemic jurkat T cells. Molecular cloning, biochemical and functional characterization. J Biol Chem 2000; 275: 39954–39963.

    Article  CAS  PubMed  Google Scholar 

  58. Southan C . A genomic perspective on human proteases. FEBS Lett 2001; 498: 214–218.

    Article  CAS  PubMed  Google Scholar 

  59. Brett D, Pospisil H, Valcarel J, Reich J, Bork P . Alternative splicing and genome complexity. Nat Genet 2002; 30: 29–30.

    Article  CAS  PubMed  Google Scholar 

  60. Shalaby FY, Levesque PC, Yang WP, Little WA, Conder ML, Jenkins-West T et al. Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. Circulation 1997; 96: 1733–1736.

    Article  CAS  PubMed  Google Scholar 

  61. Kagan A, Yu Z, Fishman GI, McDonald TV . The dominant negative LQT2 mutation A561V reduces wild-type HERG expression. J Biol Chem 2000; 275: 11241–11248.

    Article  CAS  PubMed  Google Scholar 

  62. Schroeder BC, Kubisch C, Stein V, Jentsch TJ . Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature 1998; 396: 687–690.

    Article  CAS  PubMed  Google Scholar 

  63. Jiang M, Tseng-Crank J, Tseng GN . Suppression of slow delayed rectifier current by a truncated isoform of KvLQT1 cloned from normal human heart. J Biol Chem 1997; 272: 24109–24112.

    Article  CAS  PubMed  Google Scholar 

  64. Demolombe S, Baro I, Pereon Y, Bliek J, Mohammad-Panah R, Pollard H et al. A dominant negative isoform of the long QT syndrome 1 gene product. J Biol Chem 1998; 273: 6837–6843.

    Article  CAS  PubMed  Google Scholar 

  65. Smith JS, Iannotti CA, Dargis P, Christian EP, Aiyar J . Differential expression of kcnq2 splice variants: implications to m current function during neuronal development. J Neurosci 2001; 21: 1096–1103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hugnot JP, Salinas M, Lesage F, Guillemare E, de Weille J, Heurteaux C et al. Kv8.1, a new neuronal potassium channel subunit with specific inhibitory properties towards Shab and Shaw channels. EMBO J 1996; 15: 3322–3331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Salinas M, Duprat F, Heurteaux C, Hugnot JP, Lazdunski M . New modulatory alpha subunits for mammalian Shab K+ channels. J Biol Chem 1997; 272: 24371–24379.

    Article  CAS  PubMed  Google Scholar 

  68. Raghib A, Bertaso F, Davies A, Page KM, Meir A, Bogdanov Y et al. Dominant-negative synthesis suppression of voltage-gated calcium channel cav2.2 induced by truncated constructs. J Neurosci 2001; 21: 8495–8504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hovanes K, Li TW, Munguia JE, Truong T, Milovanovic T, Lawrence Marsh J et al. Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Nat Genet 2001; 28: 3–4.

    Google Scholar 

  70. Chelli M, Alizon M . Determinants of the trans-dominant negative effect of truncated forms of the CCR5 Chemokine Receptor. J Biol Chem 2001; 276: 46975–46982.

    Article  CAS  PubMed  Google Scholar 

  71. Tiffoche C, Vaillant C, Schausi D, Thieulant ML . Novel intronic promoter in the rat ER alpha gene responsible for the transient transcription of a variant receptor. Endocrinology 2001; 142: 4106–4119.

    Article  CAS  PubMed  Google Scholar 

  72. Gil J, Rullas J, Garcia MA, Alcami J, Esteban M . The catalytic activity of dsRNA-dependent protein kinase, PKR, is required for NF-kappaB activation. Oncogene 2001; 20: 385–394.

    Article  CAS  PubMed  Google Scholar 

  73. Shepard PD, Bunney BS . Repetitive firing properties of putative dopamine-containing neurons invitro—regulation by an apamin-sensitive Ca2+-activated K+ conductance. Exp Brain Res 1991; 86: 141–150.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Contributed equally and are considered co-first authors. This study was supported by NIH grant MH59222 (KGC, JJG, MDC), Trousdale fellowship (HT), AHA pre-doctoral fellowship (VGS).

  2. K G Chandy and J J Gargus: These two authors are considered co-senior authors.

Authors and Affiliations

  1. Department of Physiology and Biophysics, Division of Human Genetics, University of California, Irvine, CA, USA

    H Tomita, V G Shakkottai, G A Gutman, G Sun, M D Cahalan, K G Chandy & J J Gargus

  2. Department of Psychiatry and Human Behavior, Division of Human Genetics, University of California, Irvine, CA, USA

    H Tomita & W E Bunney

  3. Department of Microbiology and Molecular Genetics, Division of Human Genetics, University of California, Irvine, CA, USA

    G A Gutman

  4. Department of Pediatrics, Division of Human Genetics, University of California, Irvine, CA, USA

    J J Gargus

Authors
  1. H Tomita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V G Shakkottai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G A Gutman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W E Bunney
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M D Cahalan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K G Chandy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J J Gargus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J J Gargus.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tomita, H., Shakkottai, V., Gutman, G. et al. Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia. Mol Psychiatry 8, 524–535 (2003). https://doi.org/10.1038/sj.mp.4001271

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001271

Keywords

This article is cited by

Search

Advanced search

Quick links