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

Neuronal ceroid-lipofuscinoses (NCL) are autosomal recessive disorders that form the most common group of progressive neurodegenerative diseases in ch ildren, with an incidence as high as 1 in 12,500 live births, and with appr oximately 440,000 carriers in the United States(1,2). Disease progression i s characterized by a decline in mental abilities, increased severity of unt reatable seizures, blindness, loss of motor skills and premature death. The CLN3 gene, which is responsible for Batten disease, has been positionally cloned(3). The yeast gene, denoted BTN1, encodes a non-essential protein th at is 39% identical and 59% similar to human CLN3 (ref. 4). Strains lacking Btn1p, btn1-Delta, are resistant to D-(-)-threo-2-amino-1-[p-nitrophenyl]- 1,3-propanediol (ANP) in a pH-dependent manner(5). This phenotype was compl emented by expression of human CLN3, demonstrating that yeast Btn1p and hum an CLN3 share the same function(5). Here, we report that btn1-Delta yeast s trains have an abnormally acidic vacuolar pH in the early phases of growth. Furthermore, DNA microarray analysis of BTN1 and btn1-Delta strains reveal ed differential expression of two genes, with at least one, HSP30, involved in pH control. Because Btn1p is located in the vacuole, we suggest that Ba tten disease is caused by a defect in vacuolar (lysosomal) pH control. Our findings draw parallels between fundamental biological processes in yeast a nd previously observed characteristics of neurodegeneration in humans.