THE HUMAN CHROMOSOMAL GENE FOR NECDIN, A NEURONAL GROWTH SUPPRESSOR, IN THE PRADER-WILLI-SYNDROME DELETION REGION

Necdin is a growth suppressor expressed in virtually all postmitotic n eurons in the brain. The human necdin gene, NDN, is maternally imprint ed and deleted in the Prader-Willi syndrome, a neurobehavioral contigu ous gene disorder. Here, we isolated and characterized the human chrom osomal necdin gene and its promoter region. The necdin gene is intronl ess, and it encodes a protein of 321 amino acid residues, four residue s shorter than mouse Necdin. By fluorescence in-situ hybridization ana lysis, the necdin gene was localized to chromosome 15q11.2-q12 within the Prader-Willi syndrome deletion region. CpG islands were found in a region extending from the proximal 5'-flanking sequence to the protei n-coding region. The 5'-flanking sequence, which lacks canonical TATA and CAAT boxes, possessed a promoter activity in postmitotic neurons d erived from murine embryonal carcinoma P19 cells. Methylation in vitro of HhaI CpG sites in the promoter region reduced the transcriptional activity.These results suggest that the necdin gene is silenced throug h methylation of the CpG island encompassing its promoter region. (C) 1998 Elsevier Science B.V. All rights reserved.