Myelin oligodendrocyte glycoprotein (MOG) is a transmembrane protein expressed only in the CNS and is a possible target autoantigen in multiple sclerosis (MS). To further study the association of MOG with MS, we have characterized cDNA and genomic clones encoding human MOG. The human MOG cDNA, like its rodent and bovine counterparts, encodes a mature protein containing an Ig-like domain, followed by two potential membrane-spanning regions. The intron-exon boundaries of the human MOG gene were mapped and revealed that the signal peptide is encoded by the first exon, the Ig-like domain of MOG is encoded on the second exon, whereas the remainder of the molecule is encoded by six shorter exons. In addition to the major cDNA species, a second class of MOG cDNA was isolated in which an intron was retained. Not only did this second cDNA species represent 30% of the clones analyzed (nine of 30), but RNA encoding this form was detectable by northern and reverse transcription-polymerase chain reaction analysis of the brain and spinal cord. Furthermore, we describe several restriction fragment length polymorphisms of the human MOG gene, one of which may be associated with MS susceptibility.