ABSTRACT
We previously showed that the jimpy-4J mouse mutation is located on the X chromosome, in or closely linked to the proteolipid protein (Plp) gene. The phenotype is characterized by the most severe hypomyelination of any of the naturally occurring myelin mutant mice, sharp reduction in oligodendrocyte number, and virtual absence of PLP protein. Affected animals show tremor, seizures, and die at about 24 postnatal days. We now report that sequencing of Plp genomic and cDNAs identifies a single nucleotide substitution in exon 2 that predicts an Ala38Ser substitutions in a hydrophilic region of PLP/DM20 protein close to a transmembrane domain. This mutation occurs in a very different region of the mouse Plp gene than that jimpy-msd mutations, yet all three produce qualitatively similar phenotypes.
Subject(s)
Exons/physiology , Mutation/physiology , Myelin Proteolipid Protein/genetics , Animals , Blotting, Northern , DNA/biosynthesis , DNA/genetics , DNA/isolation & purification , DNA Primers , DNA, Antisense , Demyelinating Diseases/genetics , Demyelinating Diseases/metabolism , Genome , Mice , Mice, Jimpy , Myelin Proteolipid Protein/biosynthesis , Phenotype , Polymerase Chain ReactionABSTRACT
This study describes a new sex-linked myelin mutation in the mouse, jimpy 4J (Plpjp-4J), located in or very close to the proteolipid protein (Plp) gene. The Plpjp-4J/Y phenotype includes tremor, seizures, death during the 4th postnatal week, and the most severe central nervous system hypomyelination yet described in any mouse carrying a single myelin mutation. The few myelin sheaths are present in early myelinating areas where they form clusters of thin, usually loosely wrapped membranes which show several variations of morphology at their extracellular leaflets. Numbers of mature oligodendrocytes are sharply reduced; pycnotic glial nuclei and foamy cells are numerous. Astrocytosis is a prominent feature. No PLP protein is detected by immunoblotting in Plpjp-4J/Y brain but in spinal cord a faint band is present. Myelin basic protein and characteristic myelin lipids are also sharply reduced in both brain and spinal cord. Despite the qualitative similarity of the phenotypes reported in these and previous studies, DNA analysis demonstrate that Plpjp-4J is not a recurrence of the well known Plp mouse mutations jimpy (Plpjp) or myelin synthesis deficiency (Plpjp-msd).
