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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.

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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.

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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.

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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

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Correspondence to David A. Pearce.

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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

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