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Identification of Three Forms of Human Myelin Basic Protein by Cdna Cloning

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Identification of Three Forms of Human Myelin Basic Protein by Cdna Cloning Proc. Nail. Acad. Sci. USA Vol. 83, pp. 4962-4966, July 1986 Neurobiology Identification of three forms of human myelin basic protein by cDNA cloning (myelin proteins/oligodendroglia/alternative splicing) JOHN KAMHOLZ*, FRANCESCA DE FERRAt, CARMIE PUCKETT*, AND ROBERT LAZZARINI* *Laboratory of Molecular Genetics, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892; and tThe Wistar Institute, 36th Street and Spruce, Philadelphia, PA 19104 Communicated by Roscoe 0. Brady, March 10, 1986 ABSTRACT We have isolated cDNA clones encoding three Unlike the case in the mouse, only a single MBP species separate forms of human myelin basic protein (MBP), 21.5, has been identified in human myelin. The human 18.5-kDa 18.5, and 17.2 kDa, and have determined the nucleotide MBP has been well characterized, and its amino acid se- sequence of each. The three forms share a common sequence quence has been determined directly (6). Although minor but differ by the inclusion of a 26-residue amino acid sequence bands, both larger (7) and smaller (8), are sometimes seen on near the N terminus of the 21.5-kDa protein or by the absence protein gels of human MBP, these forms have not been ofan 11-residue amino acid sequence near the C terminus ofthe isolated or characterized. 17.2-kDa protein. The sequences either added to or deleted We have examined the question ofmultiple forms ofhuman from the major 18.5-kDa MBP correspond exactly to exons 2 MBP by assembling a large collection of human MBP cDNA and 5 of the mouse MBP gene, suggesting that the human and clones and examining their structure by restriction endonu- mouse genes have similar exon structures. We have also clease mapping and nucleotide sequencing. We have identi- identified the 21.5-kDa human MBP on immunoblots using fied three types of MBP cDNAs. The most common human antisera raised to a peptide encoded by the mouse exon 2 MBP cDNA corresponds to the 18.5-kDa MBP; the amino sequence. Southern blotting studies of human genomic DNA acid sequence predicted from its nucleotide sequence match- reveal a simple pattern consistent with a single human MBP es precisely that reported for the 18.5 MBP. The two other gene. Thus, the three MBP mRNAs are likely to arise from types of MBP cDNAs encode two previously undescribed alternative splicing of a primary human MBP transcript. isoforms ofhuman MBP, one of21.5 kDa and a second of 17.2 Conservation of the 26 amino acid mouse exon 2 sequence in kDa. The 21.5-kDa human protein, like its equivalent in human MBP suggests an important role for this sequence in mouse, contains an extra 26 amino acid sequence near its N myelination. terminus. The 17.2-kDa protein is identical to the human 18.5 kDa protein but is missing 11 amino acids near its C terminus. Myelin is a multilamellar compacted membrane structure that Comparison of human and mouse MBP isoforms suggests surrounds and electrically insulates the axon, facilitating the that the human and mouse MBP genes have similar structures conduction of nerve impulses. This elaborate structure is and that the human MBPs also arise from alternative splicing synthesized and assembled by oligodendrocytes in the cen- of a primary human MBP transcript. tral nervous system (CNS) and Schwann cells in the periph- eral nervous system (PNS) (1). Myelin basic protein (MBP) MATERIALS AND METHODS constitutes 30% ofthe total myelin protein in the CNS, but it is a lesser constituent of PNS myelin. The function of MBP Preparation of RNA and DNA. Total RNA was prepared is not known, but its location on the cytoplasmic side of the from human brain by the guanidine thiocyanate/cesium myelin membrane and its tendency to self-aggregate suggest chloride method (9). Fractions enriched in mRNA were that MBP stabilizes the myelin membrane by linking the prepared from total RNA by oligo(dT) selection (10). RNA apposed cytoplasmic surfaces of the membrane sheaths. was fractionated for blot hybridization in agarose/formalde- Myelination occurs during a relatively brief time period hyde gels (10). High molecular weight DNA was prepared postnatally, and a characteristic temporal sequence for the from human placenta. synthesis of MBP prior to the onset of myelination has been Construction of Human Brain cDNA Libraries. Human described (2, 3). brain autopsy material was obtained (through the courtesy of Mouse CNS myelin contains four structurally related Lucy Rorke, Children's Hospital of Philadelphia) from a forms of MBP with molecular masses of21.5, 18.5, 17.0, and 1-day female infant who succumbed to congenital heart 14.0 kDa. We (4) and Takahashi et al. (5) have recently disease and (through the courtesy of John Sever of the determined that these four forms of mouse MBP are pro- Infectious Diseases Branch, National Institute of Neurolog- duced by alternative splicing of the primary transcript from ical and Communicative Disorders and Stroke) from a patient a single MBP gene. The gene consists of seven exons, two of with subacute sclerosing panencephalitis (SSPE). mRNA which, exons 2 and 6, are alternatively spliced, accounting was prepared from the spinal cord, the basal ganglia, and a for all four forms of mouse MBP. The largest form of MBP section ofbrain stem/cerebellum at the level of the mid pons contains the amino acid sequences encoded by all seven from the infant material and from the cerebellum of the exons. The 18.5-kDa and the 17.0-kDa proteins are homol- patient with SSPE. Expression libraries were constructed in ogous to the largest form but are missing the portions of the the vector Xgtll essentially as described by Huynh et al. (11). sequence encoded by exon 6 and exon 2, respectively. The An oligo(dT) primer was used to reverse transcribe the smallest form of MBP (14.0 kDa) lacks the sequences mRNA. The double-stranded cDNAs were ligated to EcoRI encoded by both exons 2 and 6. linkers and sized by acrylamide gel electrophoresis. The fraction identified by autoradiography as larger than 800 base The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" Abbreviations: MBP, myelin basic protein; ORF, open reading in accordance with 18 U.S.C. §1734 solely to indicate this fact. frame; kb, kilobase(s); bp, base pair(s). 4962 Downloaded by guest on September 26, 2021 Neurobiology: Kamholz et al. Proc. Natl. Acad. Sci. USA 83 (1986) 4963 pairs (bp) was recovered from the gel by elution in 20 mM Coding Region Probe Non-Coding Region Probe Tris HCl, pH 7.4/20 mM NaCl/1 mM EDTA for 24 hr, ligated Human Mouse Human Mouse to Xgt1l arms, and packaged in vitro into phage particles. The M H rRNA M H rRNA M HrRNA number of independent clones contained in each library was M H rRNA as follows: basal ganglia, 1,000,000; brain stem/cerebellum, I I t .. 4,000,000; spinal cord, 175,000; SSPE, 310,000. Partial char- I. acterization of these libraries has been previously reported 1. (12). Plaques of phages bearing MBP sequences were identified after transfer to nylon membranes by hybridization to a nick-translated insert from pdFl91, a mouse cDNA clone that -.1 contains most of the MBP coding region. The filters were hybridized in 5x SSPE (lx SSPE is 0.15 M NaCl/0.015 M 0 5x Denhardt's rw monosodium phosphate/i mM Na2EDTA), solution (lx Denhardt's solution is 0.02% Ficoll/0.02% polyvinylpyrrolidone/0.02% bovine serum albumin), 1% NaDodSO4, and 40% (vol/vol) formamide containing soni- cated salmon sperm DNA at 100 jug/ml at 420C for 16 hr, FIG. 1. Blot hybridization analysis ofhuman and mouse poly(A)+ RNA. Hybridization was carried out as described in Materials and followed by two washes in 2x SSC (lx SSC is 0.15 M Methods for library screening except that the formamide concentra- NaCl/0.015 M sodium citrate)/0.1% NaDodSO4 at room tion was 50%6 (vol/vol). The amount loaded per lane was 2 ,ug of temperature and a final wash in 2x SSC/0.1% NaDodSO4 at poly(A)+ RNA from 18-day mouse brain (M) or 4 ,ug of poly(A)+ 570C. RNA from human brain (H). The right lanes contained '4C-labeled DNA Sequence Analysis. DNA sequencing was carried out 18S and 28S rRNA markers. by the dideoxy chain termination (13) and the chemical cleavage (14) methods. foreshadowed in Fig. 1, the untranslated regions were less Immunoblotting. Immunoblotting was carried out as de- homologous (70%). The 800-bp open reading frame (ORF) in scribed by Towbin et al. (15). Peptides were synthesized and the 3' untranslated portion ofthe rat and mouse cDNAs is not antibodies were prepared as previously described (16). present in the human, although there is a 354-bp ORF General Methods. Unless otherwise stated, all methods (nucleotides 784-1137) in the human 3' sequence that over- were as described by Maniatis et al. (10). All radioactive laps a portion of the mouse ORF. Unlike the situation in the probes were prepared by nick-translation of purified DNA mouse and rat mRNAs, the second ORF of the human MBP inserts. does not contain in-frame consensus splice acceptor sites. The human and mouse ORFs share a putative 14 amino acid sequence (underlined in the figure) but are otherwise non- RESULTS homologous. The amino acid sequence deduced from the Isolation of a Human 18.5-kDa MBP cDNA.
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