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.

  • Letter
  • Published:

Action of BTN1, the yeast orthologue of the gene mutated in Batten disease

Nature Genetics volume 22, pages 55–58 (1999)Cite this article

Abstract

Neuronal ceroid-lipofuscinoses (NCL) are autosomal recessive disorders that form the most common group of progressive neurodegenerative diseases in children, with an incidence as high as 1 in 12,500 live births, and with approximately 440,000 carriers in the United States1,2. Disease progression is characterized by a decline in mental abilities, increased severity of untreatable seizures, blindness, loss of motor skills and premature death. The CLN3 gene, which is responsible for Batten disease, has been positionally cloned3. The yeast gene, denoted BTN1, encodes a non-essential protein that is 39% identical and 59% similar to human CLN3 ( ref. 4). Strains lacking Btn1p, btn1-Δ, are resistant to D-(-)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol (ANP) in a pH-dependent manner5. This phenotype was complemented by expression of human CLN3, demonstrating that yeast Btn1p and human CLN3 share the same function5. Here, we report that btn1-Δ yeast strains have an abnormally acidic vacuolar pH in the early phases of growth. Furthermore, DNA microarray analysis of BTN1 and btn1-Δ strains revealed differential expression of two genes, with at least one, HSP30, involved in pH control. Because Btn1p is located in the vacuole, we suggest that Batten disease is caused by a defect in vacuolar (lysosomal) pH control. Our findings draw parallels between fundamental biological processes in yeast and previously observed characteristics of neurodegeneration in humans.

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: Plasma membrane H+-ATPase activities and acidification of external media by actively growing normal, btn1-Δ and vph1-Δ yeast strains.
Figure 2: Comparative northern-blot analysis of HSP30, BTN2 and BTN1 mRNAs at various times during the growth of BTN1+ (open bars) and btn1-Δ (filled bars) strains.
Figure 3: Vacuolar H+-ATPase activity of isolated vacuoles at various times of growth of BTN1+ (open bars) and btn1-Δ (filled bars) strains, indicating that a higher vacuolar H+-ATPase activity may be responsible for the decreased pH in the early phase of growth in btn1-Δ strains.
Figure 4: Distribution of fluorescence in yeast cells transformed with a Btn1p-GFP construct demonstrated a vacuolar localization.

Similar content being viewed by others

References

  1. Goebel, H.H. The neuronal ceroid lipofuscinoses. J. Child. Neurol. 10, 424–437 (1995).

    Article  CAS  PubMed  Google Scholar 

  2. Banerjee, P., Dasgupta, A. Siakotas, A. & Dawson, G. Evidence for lipase abnormality: high levels of free and triacylglycerol forms of unsaturated fatty acids in neuronal ceroid-lipofuscinoses. Am. J. Med. Genet. 42, 549–554 (1992).

    Article  CAS  PubMed  Google Scholar 

  3. International Batten Disease Consortium. Isolation of a novel gene underlying Batten disease. Cell 82, 949–957 (1995).

  4. Pearce, D.A. & Sherman, F. BTN1, a yeast gene corresponding to the human gene responsible for Batten's disease, is not essential for viability, mitochondrial function, or degradation of mitochondrial ATP synthase. Yeast 13, 691–697 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  5. Pearce, D.A. & Sherman, F. A yeast model for the study of Batten disease. Proc. Natl Acad. Sci. USA 95, 6915 –6918 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pearce, D.A., Nosel, S.A. & Sherman, F. Studies of pH regulation by Btn1p, the yeast homolog of human Cln3p. Mol. Genet. Metab. 66, 320 –323 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Pearce, D.A. & Sherman, F. Investigation of Batten disease with the yeast Saccharomyces cerevisiae. Mol. Genet. Metab. 66, 314–319 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Manolson. M.F. et al. The VPH1 gene encodes a 95-kDa integral membrane polypeptide required for in vivo assembly and activity of yeast vacuolar H+-ATPase. J. Biol. Chem. 267, 14294 –14299 (1992).

    CAS  PubMed  Google Scholar 

  9. Piper, P.W., Ortiz-Calderon, C., Holyoak, C., Coote, P. & Cole, M. Hsp30, the integral plasma membrane heat shock protein of Saccharomyces cerevisiae, is a stress-inducible regulator of plasma membrane H+-ATPase. Cell Stress Chaperones 2, 12–24 ( 1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kramer, H. & Phistry, M. Mutations in the Drosophila hook gene inhibit endocytosis of the boss transmembrane ligand into multivesicular bodies. J. Cell Biol. 133, 1205 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Niedenthal, R.K., Riles, L., Johnston, M. & Hegemann, J.H. Green fluorescent protein as a marker for gene expression and subcellular localization in budding yeast. Yeast 12, 773–786 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Croopnick, J.B., Choi, H.C. & Mueller, D.M. The subcellular location of the yeast Saccharomyces cerevisiae homologue of the protein defective in juvenile form of Batten disease. Biochem. Biophys. Res. Comm. 250, 335–341 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Paulsen, I.T., Sliwinski, M.K., Nelissen, B., Goffeau, A. & Saier, M.H. Jr Unified inventory of established and putative transporters encoded within the complete genome of Saccharomyces cerevisiae. FEBS Lett. 430, 116–125 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Jarvela, I. et al. Biosynthesis and intracellular targeting of the CLN3 protein defective in Batten disease. Hum. Mol. Genet. 7, 85–90 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Haltia, M., Rapola, L., Santavuori, P. & Keranen, A. Infantile type of so-called neuronal ceroid lipofuscinosis. 2. Morphological and biochemical studies. J. Neurol. Sci. 18, 269–285 (1973).

    Article  CAS  PubMed  Google Scholar 

  16. Koenig, H., McDonald, T. & Nellhaus, G. Morphological and histochemical studies of neurolipidosis by light and electron microscopy. J. Neuropathol. Exp. Neurol. 23, 191–193 ( 1964).

    Google Scholar 

  17. Hall, N.A., Lake, B.D., Dewji, N.N. & Patrick, N.D. Lysosomal storage of subunit c of mitochondrial ATP synthase in Batten's disease. Biochem. J. 275, 269–272 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Palmer, D.N. et al. Mitochondrial ATP synthase subunit c storage in the ceroid-lipofuscinoses (Batten disease). Am. J. Med. Genet. 42, 561–567 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Cox, G.A. et al. Sodium/hydrogen exchanger gene defect in slow-wave epilepsy mutant mice. Cell 91, 139–148 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Hemenway, C.S. et al. vph6 mutants of Saccharomyces cerevisiae require calcineurin for growth and are defective in vacuolar H+-ATPase assembly. Genetics 141, 833– 844 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zinser, E. & Daum, G. Isolation and biochemical characterization of organelles from the yeast, Saccharomyces cerevisiae. Yeast 11, 493–536 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  22. Serrano, R. Characterization of the plasma membrane ATPase of Saccharomyces cerevisiae . Mol. Cell. Biochem. 22, 51 (1978).

    Article  CAS  PubMed  Google Scholar 

  23. Morano, K.A. & Klionsky, J. Differential effects of compartment deacidification on the targeting of membrane and soluble proteins to the vacuole in yeast. J. Cell Sci. 107, 2813– 2824 (1994).

    CAS  PubMed  Google Scholar 

  24. Preston, R.A., Murphy, R.F. & Jones, E.W. Assay of vacuolar pH in yeast and identification of acidification-defective mutants. Proc. Natl Acad. Sci. USA 86, 7027–7031 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. DeRisi, J.L., Iyer, V.R. & Brown, P.O. Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278, 680– 686 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Sambrook, J., Fritsch, E.F. & Maniatis, T. in Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1989).

    Google Scholar 

Download references

Acknowledgements

We thank D.M. Mueller for sharing results before publication; T. Langer for providing unpublished results with Btn1p-GFP; E.W. Jones for the VPH1+ and vph1-Δ strains; S. Gibson for technical assistance in measuring vacuolar pH; and D. Goldfarb for the use of a fluorescent microscope. Supported by NIH grant R01 NS36610 and NCI grant CA 36856.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, 14642, New York, USA

    David A. Pearce, Seth A. Nosel, Biswadip Das & Fred Sherman

  2. Department of Genetics, Stanford School of Medicine, L311, Stanford, 94305-5120, California, USA

    Tracy Ferea

Authors
  1. David A. Pearce
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tracy Ferea
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seth A. Nosel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Biswadip Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fred Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David A. Pearce.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pearce, D., Ferea, T., Nosel, S. et al. Action of BTN1, the yeast orthologue of the gene mutated in Batten disease. Nat Genet 22, 55–58 (1999). https://doi.org/10.1038/8861

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/8861

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing