We have isolated cDNA clones encoding the four different forms of mouse myelin basic protein (MBP) and have analyzed the structure of the MBP gene. The three larger forms of MBP differ from the smallest by the inclusion of either or both of two short amino acid sequences at positions 57 and 124 of the smallest protein. The mouse genome contains a single MBP gene comprised of seven exons. The two amino acid sequences present only in the larger MBPs are encoded by separate exons. Furthermore, all exons in the coding region begin or end in complete codons so that alternative splicing does not alter the reading frame. We conclude that the four forms of this myelin protein are encoded in separate mRNAs, each derived by a simple alternative splicing of the primary MBP gene transcript. Comparison of the amino acid sequence encoded by each exon with a recent model of the secondary structure of MBP suggests that each of the seven exons encodes one or two of the predicted structural motifs of the protein.

Shiverer (shi) is an autosomal recessive mutation in the mouse characterized by an almost total lack of central nervous system myelin. While small amounts of other myelin components are present in the brain of the shi mouse, the four forms of myelin basic protein (MBP) are not detectable. Previous investigations by us and others indicate that the MBP gene has undergone a major rearrangement in the shi mutant. Herein, we report in detail the nature and extent of the rearrangement: a 20-kilobase region within the MBP gene is missing in the mutant. We map the 5' breakpoint ofthe deletion to the second intron and the 3' breakpoint to a site 2 kilobases beyond the last MBP exon. The junction of the upstream and downstream portions of the gene contains only one nucleotide not accounted for by the wild-type MBP gene sequence. The 3' side of the deletion occurs in the 3rd of 11 tandem repeats of a 31-base-pair sequence. This region is rich in alternating purine and pyrimidine stretches, sequences that have been associated with both Z-DNA structures and gene rearrangements. Mammalian oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS) produce a highly specialized multilamellar myelin membrane that surrounds the neuronal axons and greatly facilitates conduction of electrical impulses (reviewed in ref. 1). The myelin of the CNS has a relatively simple composition in which a family of closely related myelin basic proteins (MBPs) accounts for 30-40% of the total protein in the sheath (reviewed in ref. 2). Peripheral nervous system myelin contains a smaller and dispensable amount of the same MBPs (3, 4). Recent work by us (5) and others (6) has shown that a single gene encodes the family of MBPs and that the various forms of the MBPs are generated by a mechanism of alternative splicing of the mRNA.A number of mutations have been identified in mice that affect oligodendrocyte function and/or Schwann cell function and, consequently, lead to dysmyelination in the CNS and/or the PNS (reviewed in ref. 7). The shiverer (shi) mutation is autosomal recessive and is characterized by the onset of tremors at about the 12th day of life, seizures at later times, and a progressive deterioration ending in an early death (8, 9). The mutation principally affects oligodendrocyte functions and the CNS of the shi mice is almost entirely devoid of myelin membrane (10). The normal amount of myelin is present in the PNS of these animals, but differences in its structure have been noted (4,11,12). The primary defect in shi mice appears to be the absence of MBP (13). By radioimmune assay, MBP levels in shi mice are <0.1% that of wild type (14).The shi allele has been mapped to chromosome 18 by Sidman et al. (15) using classic genetic techniques. The gene encoding the MBP family has also been mapped to chromosome 18 by in situ hybridization and Southern blot analysis of DNA isolated from mouse-hamster somatic cell hybrids (16). Recent work by Roach et al. (17,18) and by us (5) demonst...