Letter to the Editor

Jimpymsd Mouse Mutation and ConnatalPelizaeus-Merzbacher Disease

To the Editor:

Proteolipid protein (PLP) abnormalities cause dys-myelination in the central nervous system, with sev-eral levels of severity [Hodes et al., 1993]. The jimpymouse, a well-known model of PLP abnormalities, hasbeen examined in greater detail than any other animalmodel, and has provided many clues to the genetic andcellular dysfunctions in human Pelizaeus-Merzbacherdisease (PMD) [Hudson et al., 1989].

There are two other mouse models of PLP abnormali-ties, jimpymsd and rumpshaker mouse. The phenotypeof the jimpymsd allele, the A242V mutation, is almostindistinguishable from that of jimpy and has been usedas a model of human connatal type of PMD in researchinvestigations [Gow and Lazzarini, 1996]. In contrast,the rumpshaker allele I186T is characterized by milddisease with hypomyelination, and was identified inhumans with spastic paraplegia [Kobayashi et al., 1994].

A Japanese male infant was the only child of non-consanguineous and healthy parents. Pendular nystag-mus and psychomotor developmental delay were notedby 4 months. At 7 months, an abnormally high inten-sity of white matter was demonstrated by T2-weightedmagnetic resonance imaging (MRI), and an abnormaldisappearance after wave III was also detected by au-ditory brain-stem responses (ABR). He died suddenlyat 9 months, and dysmyelinated white matter of thebrain was observed at autopsy.

DNA was prepared from peripheral blood and ampli-fied by PCR with sets of primers for all seven exons ofthe PLP gene [Doll et al., 1992]. The amplified productswere subcloned and sequenced. A C725T transition, re-sulting in an A242V substitution, was found in exon 6.There were no mutations in the other six exons. Thisbase change abolished a BbvI restriction enzyme site(GCAGC(N)8). To confirm the mutation, the PCR prod-ucts were digested with BbvI at 37°C overnight. The

reaction samples were electrophoresed on 12% acryl-amide gel and visualized by silver staining (Fig. 1). Themutation of the index case was confirmed; the motherwas a carrier.

This is a new mutation in exon 6 of the human PLPgene, but identical to the jimpymsd mutation, showingthat this mutation causes severe hypomyelination inhumans and mice. Consequently, the jimpymsd mouseis clinically and pathologically identical with connatalPMD. This observation supports many investigationswhich use jimpymsd as a model for connatal PMD.

REFERENCES

Doll R, Natowicz MR, Schiffmann R, Smith FI (1992): Molecular diagnos-tics for myelin proteolipid protein gene mutations in Pelizaeus-Merzbacher disease. Am J Hum Genet 51:161–169.

Gow A, Lazzarini RA (1996): A cellular mechanism governing the severityof Pelizaeus-Merzbacher disease. Nat Genet 13:422–428.

Hodes ME, Pratt VM, Dlouhy SR (1993): Genetics of Pelizaeus-Merzbacherdisease. Dev Neurosci 15:383–394.

Hudson LD, Puckett C, Berndt J, Chan J, Gencic S (1989): Mutation of theproteolipid protein gene PLP in a human X chromosome-linked myelindisorder. Proc Natl Acad Sci USA 86:8128–8131.

Kobayashi H, Hoffman EP, Marks HG (1994): The rumpshaker mutation inspastic paraplegia. Nat Genet 7:351–352.

*Correspondence to: Toshiyuki Yamamoto, M.D., Gene Re-search Center, Tottori University, 86 Nishi-machi, Yonago 683,Japan. E-mail: tyamamot@grape.med.tottori-u.ac.jp

Received 12 August 1997; Accepted 3 October 1997

Fig. 1. BbvI digestion products of the PCR-amplified exon 6. A 60-bpfragment, which was normally digested into 45-bp and 15-bp (not visible)fragments in the father and control (C), was not digested in the patient.The mother showed both fragments of 45 bp and 60 bp. M, size marker;pBR322/MspI digest.

American Journal of Medical Genetics 75:439–440 (1998)

© 1998 Wiley-Liss, Inc.

Toshiyuki Yamamoto*Eiji NanbaHaidi ZhangGene Research CenterTottori UniversityYonago, Japan

Masayuki SasakiHirohumi KomakiDepartment of Child NeurologyNational Center Hospital for Mental,

Nervous, and Muscular DisordersNational Center of Neurology and PsychiatryTokyo, Japan

Kenzo TakeshitaDivision of Child NeurologyInstitute of Neurological SciencesFaculty of MedicineTottori UniversityYonago, Japan

440 Yamamoto et al.