Jimpymsd mouse mutation and connatal Pelizaeus-Merzbacher disease

Proteolipid protein (PLP) abnormalities cause dysmyelination in the central nervous system, with several levels of severity [Hodes et al., 1993].The jimpy mouse, a well-known model of PLP abnormalities, has been examined in greater detail than any other animal model, and has provided many clues to the genetic and cellular dysfunctions in human Pelizaeus-Merzbacher disease (PMD) [Hudson et al., 1989].There are two other mouse models of PLP abnormalities, jimpy msd and rumpshaker mouse.The phenotype of the jimpy msd allele, the A242V mutation, is almost indistinguishable from that of jimpy and has been used as a model of human connatal type of PMD in research investigations [Gow and Lazzarini, 1996].In contrast, the rumpshaker allele I186T is characterized by mild disease with hypomyelination, and was identified in humans with spastic paraplegia [Kobayashi et al., 1994].A Japanese male infant was the only child of nonconsanguineous and healthy parents.Pendular nystagmus and psychomotor developmental delay were noted by 4 months.At 7 months, an abnormally high intensity of white matter was demonstrated by T2-weighted magnetic resonance imaging (MRI), and an abnormal disappearance after wave III was also detected by auditory brain-stem responses (ABR).He died suddenly at 9 months, and dysmyelinated white matter of the brain was observed at autopsy.DNA was prepared from peripheral blood and amplified by PCR with sets of primers for all seven exons of the PLP gene [Doll et al., 1992].The amplified products were subcloned and sequenced.A C725T transition, resulting in an A242V substitution, was found in exon 6.There were no mutations in the other six exons.This base change abolished a BbvI restriction enzyme site (GCAGC(N) 8 ).To confirm the mutation, the PCR products were digested with BbvI at 37°C overnight.The reaction samples were electrophoresed on 12% acrylamide gel and visualized by silver staining (Fig. 1).The mutation of the index case was confirmed; the mother was a carrier.This is a new mutation in exon 6 of the human PLP gene, but identical to the jimpy msd mutation, showing that this mutation causes severe hypomyelination in humans and mice.Consequently, the jimpy msd mouse is clinically and pathologically identical with connatal PMD.This observation supports many investigations which use jimpy msd as a model for connatal PMD.