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. 1989 Oct;86(20):8128–8131. doi: 10.1073/pnas.86.20.8128

Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder.

L D Hudson 1, C Puckett 1, J Berndt 1, J Chan 1, S Gencic 1
PMCID: PMC298228  PMID: 2479017

Abstract

Myelin is a highly specialized membrane unique to the nervous system that ensheaths axons to permit the rapid saltatory conduction of impulses. The elaboration of a compact myelin sheath is disrupted in a diverse spectrum of human disorders, many of which are of unknown etiology. The X chromosome-linked human disorder Pelizaeus-Merzbacher disease is a clinically and pathologically heterogeneous group of disorders that demonstrate a striking failure of oligodendrocyte differentiation. This disease appears pathologically and genetically to be similar to the disorder seen in the dysmyelinating mouse mutant jimpy, which has a point mutation in the gene encoding an abundant myelin protein, proteolipid protein (PLP). We report that the molecular defect in one Pelizaeus-Merzbacher family is likewise a point mutation in the PLP gene. A single T----C transition results in the substitution of a charged amino acid residue, arginine, for tryptophan in one of the four extremely hydrophobic domains of the PLP protein. The identification of a mutation in this Pelizaeus-Merzbacher family should facilitate the molecular classification and diagnosis of these X chromosome-linked human dysmyelinating disorders.

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Selected References

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  1. Campagnoni A. T., Macklin W. B. Cellular and molecular aspects of myelin protein gene expression. Mol Neurobiol. 1988 Spring;2(1):41–89. doi: 10.1007/BF02935632. [DOI] [PubMed] [Google Scholar]
  2. Campagnoni A. T. Molecular biology of myelin proteins from the central nervous system. J Neurochem. 1988 Jul;51(1):1–14. doi: 10.1111/j.1471-4159.1988.tb04827.x. [DOI] [PubMed] [Google Scholar]
  3. Dautigny A., Alliel P. M., d'Auriol L., Pham Dinh D., Nussbaum J. L., Galibert F., Jollès P. Molecular cloning and nucleotide sequence of a cDNA clone coding for rat brain myelin proteolipid. FEBS Lett. 1985 Aug 19;188(1):33–36. doi: 10.1016/0014-5793(85)80869-3. [DOI] [PubMed] [Google Scholar]
  4. Diehl H. J., Schaich M., Budzinski R. M., Stoffel W. Individual exons encode the integral membrane domains of human myelin proteolipid protein. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9807–9811. doi: 10.1073/pnas.83.24.9807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Fahim S., Riordan J. R. Lipophilin (PLP) gene in X-linked myelin disorders. J Neurosci Res. 1986;16(1):303–310. doi: 10.1002/jnr.490160125. [DOI] [PubMed] [Google Scholar]
  6. Gencic S., Abuelo D., Ambler M., Hudson L. D. Pelizaeus-Merzbacher disease: an X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein. Am J Hum Genet. 1989 Sep;45(3):435–442. [PMC free article] [PubMed] [Google Scholar]
  7. Higuchi R., von Beroldingen C. H., Sensabaugh G. F., Erlich H. A. DNA typing from single hairs. Nature. 1988 Apr 7;332(6164):543–546. doi: 10.1038/332543a0. [DOI] [PubMed] [Google Scholar]
  8. Hudson L. D., Berndt J. A., Puckett C., Kozak C. A., Lazzarini R. A. Aberrant splicing of proteolipid protein mRNA in the dysmyelinating jimpy mutant mouse. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1454–1458. doi: 10.1073/pnas.84.5.1454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hudson L. D., Friedrich V. L., Jr, Behar T., Dubois-Dalcq M., Lazzarini R. A. The initial events in myelin synthesis: orientation of proteolipid protein in the plasma membrane of cultured oligodendrocytes. J Cell Biol. 1989 Aug;109(2):717–727. doi: 10.1083/jcb.109.2.717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ikenaka K., Furuichi T., Iwasaki Y., Moriguchi A., Okano H., Mikoshiba K. Myelin proteolipid protein gene structure and its regulation of expression in normal and jimpy mutant mice. J Mol Biol. 1988 Feb 20;199(4):587–596. doi: 10.1016/0022-2836(88)90303-8. [DOI] [PubMed] [Google Scholar]
  11. Koeppen A. H., Ronca N. A., Greenfield E. A., Hans M. B. Defective biosynthesis of proteolipid protein in Pelizaeus-Merzbacher disease. Ann Neurol. 1987 Feb;21(2):159–170. doi: 10.1002/ana.410210208. [DOI] [PubMed] [Google Scholar]
  12. Lemke G. Unwrapping the genes of myelin. Neuron. 1988 Sep;1(7):535–543. doi: 10.1016/0896-6273(88)90103-1. [DOI] [PubMed] [Google Scholar]
  13. Macklin W. B., Campagnoni C. W., Deininger P. L., Gardinier M. V. Structure and expression of the mouse myelin proteolipid protein gene. J Neurosci Res. 1987;18(3):383–394. doi: 10.1002/jnr.490180302. [DOI] [PubMed] [Google Scholar]
  14. Macklin W. B., Gardinier M. V., King K. D., Kampf K. An AG----GG transition at a splice site in the myelin proteolipid protein gene in jimpy mice results in the removal of an exon. FEBS Lett. 1987 Nov 2;223(2):417–421. doi: 10.1016/0014-5793(87)80331-9. [DOI] [PubMed] [Google Scholar]
  15. Mattei M. G., Alliel P. M., Dautigny A., Passage E., Pham-Dinh D., Mattei J. F., Jollès P. The gene encoding for the major brain proteolipid (PLP) maps on the q-22 band of the human X chromosome. Hum Genet. 1986 Apr;72(4):352–353. doi: 10.1007/BF00290964. [DOI] [PubMed] [Google Scholar]
  16. Matthieu J. M., Widmer S., Herschkowitz Jimpy, an anomaly of, myelin maturation. Biochemical study of myelination phases. Brain Res. 1973 Jun 15;55(2):403–412. doi: 10.1016/0006-8993(73)90305-3. [DOI] [PubMed] [Google Scholar]
  17. Molineaux S. M., Engh H., de Ferra F., Hudson L., Lazzarini R. A. Recombination within the myelin basic protein gene created the dysmyelinating shiverer mouse mutation. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7542–7546. doi: 10.1073/pnas.83.19.7542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Morello D., Dautigny A., Pham-Dinh D., Jollès P. Myelin proteolipid protein (PLP and DM-20) transcripts are deleted in jimpy mutant mice. EMBO J. 1986 Dec 20;5(13):3489–3493. doi: 10.1002/j.1460-2075.1986.tb04674.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Naismith A. L., Hoffman-Chudzik E., Tsui L. C., Riordan J. R. Study of the expression of myelin proteolipid protein (lipophilin) using a cloned complementary DNA. Nucleic Acids Res. 1985 Oct 25;13(20):7413–7425. doi: 10.1093/nar/13.20.7413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Nave K. A., Bloom F. E., Milner R. J. A single nucleotide difference in the gene for myelin proteolipid protein defines the jimpy mutation in mouse. J Neurochem. 1987 Dec;49(6):1873–1877. doi: 10.1111/j.1471-4159.1987.tb02449.x. [DOI] [PubMed] [Google Scholar]
  21. Nave K. A., Lai C., Bloom F. E., Milner R. J. Jimpy mutant mouse: a 74-base deletion in the mRNA for myelin proteolipid protein and evidence for a primary defect in RNA splicing. Proc Natl Acad Sci U S A. 1986 Dec;83(23):9264–9268. doi: 10.1073/pnas.83.23.9264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Puckett C., Hudson L., Ono K., Friedrich V., Benecke J., Dubois-Dalcq M., Lazzarini R. A. Myelin-specific proteolipid protein is expressed in myelinating Schwann cells but is not incorporated into myelin sheaths. J Neurosci Res. 1987;18(4):511–518. doi: 10.1002/jnr.490180402. [DOI] [PubMed] [Google Scholar]
  23. Roach A., Takahashi N., Pravtcheva D., Ruddle F., Hood L. Chromosomal mapping of mouse myelin basic protein gene and structure and transcription of the partially deleted gene in shiverer mutant mice. Cell. 1985 Aug;42(1):149–155. doi: 10.1016/s0092-8674(85)80110-0. [DOI] [PubMed] [Google Scholar]
  24. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  25. Skoff R. P. Increased proliferation of oligodendrocytes in the hypomyelinated mouse mutant-jimpy. Brain Res. 1982 Sep 23;248(1):19–31. doi: 10.1016/0006-8993(82)91143-x. [DOI] [PubMed] [Google Scholar]
  26. Tabor S., Richardson C. C. DNA sequence analysis with a modified bacteriophage T7 DNA polymerase. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4767–4771. doi: 10.1073/pnas.84.14.4767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Watanabe I., Patel V., Goebel H. H., Siakotos A. N., Zeman W., DeMyer W., Dyer J. S. Early lesion of Pelizaeus-Merzbacher disease: electron microscopic and biochemical study. J Neuropathol Exp Neurol. 1973 Apr;32(2):313–333. doi: 10.1097/00005072-197304000-00010. [DOI] [PubMed] [Google Scholar]
  28. Wilkus R. J., Farrell D. F. Electrophysiologic observations in the classical form of Pelizaeus-Merzbacher disease. Neurology. 1976 Nov;26(11):1042–1045. doi: 10.1212/wnl.26.11.1042. [DOI] [PubMed] [Google Scholar]
  29. Willard H. F., Riordan J. R. Assignment of the gene for myelin proteolipid protein to the X chromosome: implications for X-linked myelin disorders. Science. 1985 Nov 22;230(4728):940–942. doi: 10.1126/science.3840606. [DOI] [PubMed] [Google Scholar]
  30. ZEMAN W., DEMYER W., FALLS H. F. PELIZAEUS-MERZBACHER DISEASE. A STUDY IN NOSOLOGY. J Neuropathol Exp Neurol. 1964 Apr;23:334–354. doi: 10.1097/00005072-196404000-00008. [DOI] [PubMed] [Google Scholar]

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