IDENTIFICATION OF A HUMAN HOMOLOG OF THE DROSOPHILA NEURALIZED GENE WITHIN THE 10Q25.1 MALIGNANT ASTROCYTOMA DELETION REGION

The loss of chromosome 10 is the most frequent genetic alteration foun d in malignant astrocytomas, In particular, the long arm of chromosome 10 was previously reported to have two or more common deletion region s where tumor suppressor genes may be located, In this study, we perfo rmed deletion mapping of 44 malignant astrocytomas using 12 microsatel lite markers on chromosome 10q and demonstrated that the minimal commo n region of loss of heterozygosity (LOH) was present between D10S192 a nd D10S566 localized at 10q25.1. Subsequently, we have identified a no vel gene, termed h-neu, within the region frequently deleted and found that h-neu encodes a protein with strong homology to the Drosophila n euralized (D-neu) protein, Northern blot and RT-PCR analyses revealed that h-neu mRNA was expressed at very low levels in human malignant as trocytoma tissues and the majority of glioma cell lines examined, whil e normal brains expressed h-neu transcript, Furthermore, DNA sequencin g analysis of the h-neu transcript revealed one of the glioma cell lin es, U251MG, had a single nucleotide substitution which resulted in an amino acid change from glycine (GGC) to serine (AGC) at codon 253, The D-neu gene is known to serve a critical function in neurogenesis in D rosophila, and loss-of-function mutations produce hyperplasia of primi tive neuronal cells, These observations led us to hypothesize that h-n eu gene plays a role in determination of cell fate in the human centra l nervous system and may act as a tumor suppressor whose inactivation could be associated with malignant progression of astrocytic tumors.