IDENTIFICATION AND LOCALIZATION OF THE GENE FOR EXTL, A 3RD MEMBER OFTHE MULTIPLE EXOSTOSES GENE FAMILY

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by multiple bony outgrowths From the juxtaepiphyseal reg ion of long bones. In a small proportion of cases, these exostoses pro gress to malignant chondrosarcomas. Genetic linkage of this disorder h as been described to three independent loci on chromosomes 8q24.1 (EXT 1), 11p11-13 (EXT2), and 19p (EXT-3). The EXT1 and EXT2 genes were iso lated recently and show extensive sequence homology to each other. The se genes are deleted in exostoses-derived tumors, supporting the hypot hesis that they encode tumor suppressors. We have identified a third g ene that shows striking sequence similarity to both EXT1 and EXT2 at t he nucleotide and amino acid sequence levels, and have derived its ent ire coding sequence. Although the mRNA transcribed from this gene is s imilar in size to that from EXT1 and EXT2, its pattern of expression i s quite different. We have localized this gene by fluorescence in situ hybridization to metaphase chromosomes and by whole genome radiation hybrid mapping to chromosome 1p36.1 between D15458 and DIS511, a regio n that frequently shows loss of heterozygosity in a variety of tumor t ypes. This gene, EXTL (for EXT-like), is therefore a new member of the EXT gene family and is a potential candidate for several disease phen otypes.