Novel members of the low density lipoprotein receptor family were identified in human endothelial and vascular smooth muscle cells utilizing a homology-cloning strategy. Four novel mRNA transcripts could be identified as isoforms of the apolipoprotein E receptor 2 (apoEr2): one form lacking three ligand binding repeats (nucleotides 497-883) but containing a novel ligand binding repeat adjacent to a unique cysteine-rich domain preceding the epidermal growth factor precursor domain of apoEr2, forms lacking the O-linked sugar domain, and forms containing a 59-amino acid deletion within the cytoplasmic tail. By fluorescence in situ hybridization for chromosome mapping, we could confirm that the novel alternative forms of apoEr2 are splice variants of transcripts from a single copy gene on chromosome 1p34. To analyze whether the different splice variants of apoEr2 mRNA are expressed in a splice variant-specific pattern, we concentrated on the central nervous system, where high expression of apoEr2 has been described originally. By means of splice variant-specific in situ hybridization, we could confirm that apoEr2 mRNA is abundantly expressed in brain tissue and, with exception of the newly identified ligand binding domain, all mRNA splice variants exhibited a similar expression pattern. The mRNA of the newly identified ligand binding domain, however, was expressed in brain only in cells of the vascular wall, confirming data from Northern blotting, where the mRNA of the newly identified ligand binding domain was found in several tissues but was absent in brain tissue.