A novel brain-specific gene, neuronal double zinc finger protein (ZNF231), was cloned and mapped. We used the high-density cDNA filter method to analyze the gene-expression profile in brains with multiple system atrophy (MSA). MSA is a sporadic progressive neurodegenerative disease characterized clinically by cerebellar symptoms, parkinsonism, autonomic dysfunction, or their various combinations, but its pathogenesis has yet to be clarified. In total, 8300 cDNA clones were screened, and a novel gene, ZNF231, was identified, whose expression was elevated in cerebella of patients with MSA. Its transcript is approximately 16 kb long and encodes an open reading frame of 3926 amino acid residues that has several interesting motifs; two glycine-proline dipeptide repeats (aa 22-32 and aa 61-74), a pair of homologous C8 double zinc finger motifs (aa 169-226 and aa 465-521), a leucine zipper motif (aa 561-582), a SH3 domain-binding motif (aa 825-831), two nuclear targeting signals (aa 1011-1028 and aa 1071-1091), two glutamine-rich domains (aa 2428-2473 and aa 3775-3804), and a histidine-rich domain (aa 3597-3682). These features suggest that the new gene encodes a nuclear protein or transcription regulator. Northern blot and RT-PCR analyses showed that its expression is specific to the brain and apparently restricted to the neurons. Elevation of ZNF231 expression may be involved in the pathogenesis of multiple system atrophy. The gene for ZNF231 is located on chromosome 3p21. (C) 1998 Academic Press.