There are several X-linked diseases in animals and at least one in man in which there is a failure of CNS myelination. We have recently cloned cDNAs for lipophilin (PLP) with which PLP sequences were localized to a region of the long arm of the X chromosome (Xq13-q22 in man) close to the jimpy (jp) locus in that mouse mutant. The present communication pursues the postulate that some of this class of diseases may involve mutations at the PLP locus. Blot hybridization analysis of PLP mRNA levels revealed a five-to tenfold reduction in the brains of hemizygous jp/Y mice. The major PLP mRNA species of those mice was also reduced in size. However, Southern blots of jp DNA digested with many different restriction enzymes failed to detect major deletions or other rearrangements in the PLP gene. A human PLP cDNA was isolated and employed to similarly analyze DNA from four patients diagnosed as having Pelizaeus-Merzbacher disease. In one of these four a significant rearrangement of the PLP gene was found. These findings suggest that there may be alterations in the PLP gene in both jp mouse and Pelizaeus-Merzbacher disease.