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The leptin receptor (OB-R) is a single membrane- spanning protein that mediates the weight-regulatory effects of leptin (OB protein). Several mRNA splice variants have been described which either encode OB-R proteins with cytoplasmic domains of different length or the OB-R and B219/OBR variants, which have different 5'-untranslated regions. Here we report evidence for the synthesis of a human mRNA splice variant of the OB-R gene that potentially encodes a novel protein, leptin receptor gene-related protein (OB-RGRP), which displays no sequence similarity to the leptin receptor itself. This OB-RGRP transcript contains the first two OB-R gene 5'-untranslated exons, but then is alternatively spliced to two novel exons which were mapped to a yeast artificial chromosome containing the leptin receptor gene. First identified by analysis of a large human expressed sequence tag database, the OB-RGRP transcript has now also been found in human and mouse tissues by the use of PCR. Preliminary experiments suggest that OB-RGRP and the OB-R variants share similar patterns of expression that are distinct from that of the B219/OBR variant. OB-RGRP is highly homologous to putative open reading frames in both yeast and Caenorhabditis elegans , suggesting a phylogenetically conserved role for this novel protein.