Isolation and characterization of a human homologue of the latrophilin gene from a region of 1p31.1 implicated in breast cancer

We have identified a region of chromosome 1p31.1 that shows high frequency loss of heterozygosity (LOH) in human breast cancer. This region forms part of a 7 Mb YAC/BAC contig, In order to identify candidate sequences, mutati on of which might contribute to the development of disease, we have carried out mapping studies of ESTs localized to 1p31.1. This analysis, coupled wi th library screening and a modified 5' RACE-PCR strategy, resulted in the i dentification and characterization of a novel gene (LPHH1) which is located adjacent to the smallest region of overlapping loss (SRO) seen in tumours, The 4209 bp open reading frame of the 7 kb LPHH1 transcript encodes a pept ide which shows approximately 65% identity to rat latrophilin, a G-coupled, seven span transmembrane protein, which binds alpha-latrotoxin. In the hum an sequence, whilst conservation of the transmembrane domain is high, the i ntra- and extracellular domains show two regions of variable structure, whi ch are presumably generated by alternative splicing. Surprisingly, while ex pression of the rat gene is tightly restricted to neurological and perhaps some endocrine cells, the human sequence appears to be expressed very widel y in all normal tissues tested. Northern and RT-PCR analysis of a panel of tumour cell lines showed that LPHH1 expression was variable, apparently ele vated in some lines and absent or markedly reduced in others. Furthermore, characterization of the range of transcripts encoded in a breast tumour cel l line, compared to normal breast, suggested that gene product variability was higher in the tumour.