Human FRAG1 Encodes a Novel Membrane-Spanning Protein That Localizes to Chromosome 11p15.5, a Region of Frequent Loss of Heterozygosity in Cancer

Abstract

We have previously identified a chromosomal rearrangement between fibroblast growth factor receptor 2 (FGFR2) and a novel gene, FRAG1, in a rodent model of osteosarcoma. To assess the potential role of FRAG1 in disease further, we have isolated cDNA and genomic clones of human FRAG1. Sequence analysis of the cDNA revealed the presence of an insertion not contained in the original FRAG1 sequence. This insertion in human FRAG1 encoded a region highly homologous to and immediately following the first 55 amino acids of the protein, indicating the presence of a repetitive domain within FRAG1, designated the FRAG1 homology (FH) domain. Analysis of FRAG1 gene structure revealed that the FH domains were encoded by tandem duplicated exons. Database searches identified several transmembrane proteins displaying homology to the FH domain of FRAG1. In addition, hydropathy analysis predicted FRAG1 to encode an integral membrane protein with multiple membrane-spanning segments. FRAG1 mRNA was ubiquitously expressed in human adult tissues and several tumor cell lines at varying levels of abundance. Human FRAG1 was mapped by fluorescence in situ hybridization and radiation hybrid analysis to chromosome 11 at band p15.5, a region implicated in Beckwith–Wiedemann syndrome and a region of frequent loss of heterozygosity in multiple tumor types. These results suggest that FRAG1 may be a useful candidate gene for genetic disorders associated with alterations at 11p15.5.