A major cytogenetic subgroup of lipomas is characterized by recurrent chromosome aberrations, mainly translocations, that involve chromosome segment 12q13-q15. Multiple chromosomes have been found as the translocation partners of chromosome 12 but 3q27-q28 is preferentially involved. In previous studies, it has been shown that the high mobility group (HMG) protein gene HMGIC at 12q15 is consistently rearranged as a consequence of these translocations. Here, we report the identification and characterization of the chromosome 3-derived translocation partner gene, which we have designated LPP (lipoma preferred partner gene). Using 3'-RACE analysis of HMGIC fusion transcripts in lipoma cell line Li-501/SV40, ectopic genetic sequences were obtained, which by CASH (chromosome assignment using somatic cell hybrids) and FISH (fluorescence in situ hybridization) analysis were found to originate from chromosome segment 3q27-q28. In Northern blot analysis, an mRNA of over 10 kb was detected by these ectopic sequences in a variety of human tissues but not in brain and peripheral blood leukocytes. Upon partial cDNA cloning, features of the genetic organization of LPP were established. The gene was found to span a genomic region of over 400 kb. Nucleotide sequence analysis of a composite cDNA of LPP revealed an open reading frame of 1836 nucleotides encoding a proline-rich protein containing a leucine-zipper motif in its amino-terminal region and three LIM domains in its carboxy-terminal region. The LPP-encoded protein should be classified as a novel member of the group 3 proteins of the LIM protein gene family. Using reverse transcriptase combined with polymerase chain reactions in the analysis of a number of lipoma cell lines and primary lipomas, it appeared that LPP is frequently rearranged also in cases without a cytogenetically detectable involvement of 3q27-q28. Two alternative HMGIC/LPP hybrid transcripts have been detected; the difference between them is mainly the presence of either two or three LIM domains in the predicted HMGI-C/LPP fusion proteins.