Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Sep 1;88(17):7562–7566. doi: 10.1073/pnas.88.17.7562

Pelizaeus-Merzbacher disease: a valine to phenylalanine point mutation in a putative extracellular loop of myelin proteolipid.

D Pham-Dinh 1, J L Popot 1, O Boespflug-Tanguy 1, P Landrieu 1, J F Deleuze 1, J Boué 1, P Jollès 1, A Dautigny 1
PMCID: PMC52341  PMID: 1715570

Abstract

In the central nervous system, myelin proteolipid protein isoforms (PLP and DM20) play an essential structural role in myelination. It has been shown in several species that myelination is impaired by molecular defects resulting from single base mutations in the PLP gene. We have used DNA amplification by polymerase chain reaction to study the PLP gene coding regions from 17 patients in 15 unrelated families with similar Pelizaeus-Merzbacher phenotype. In one case amplification of peripheral nerve PLP/DM20 cDNAs revealed that a silent T----C transition was unrelated to the disease. In one family a nonsilent mutation was identified that leads to a phenylalanine substitution for valine-218 in PLP/DM20 proteins. We investigated the inheritance of the mutant allele in 19 subjects of this four-generation family and found a strict cosegregation of the Phe218 substitution with transmission and expression of the disease. The effect of the Val218----Phe mutation is discussed in the frame of a recently suggested topological model of PLP/DM20, according to which Val218 is part of an extracellular loop that connects the last two of four membrane-spanning alpha-helices.

Full text

PDF
7562

Images in this article

7564Image
on p.7564
7564Image
on p.7564
7565Image
on p.7565
7565Image
on p.7565
7565Image
on p.7565

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bartlett W. P., Knapp P. E., Skoff R. P. Glial conditioned medium enables jimpy oligodendrocytes to express properties of normal oligodendrocytes: production of myelin antigens and membranes. Glia. 1988;1(4):253–259. doi: 10.1002/glia.440010404. [DOI] [PubMed] [Google Scholar]
  2. Bizzozero O. A., Good L. K., Evans J. E. Cysteine-108 is an acylation site in myelin proteolipid protein. Biochem Biophys Res Commun. 1990 Jul 16;170(1):375–382. doi: 10.1016/0006-291x(90)91284-y. [DOI] [PubMed] [Google Scholar]
  3. Boison D., Stoffel W. Myelin-deficient rat: a point mutation in exon III (A----C, Thr75----Pro) of the myelin proteolipid protein causes dysmyelination and oligodendrocyte death. EMBO J. 1989 Nov;8(11):3295–3302. doi: 10.1002/j.1460-2075.1989.tb08490.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boulloche J., Aicardi J. Pelizaeus-Merzbacher disease: clinical and nosological study. J Child Neurol. 1986 Jul;1(3):233–239. doi: 10.1177/088307388600100310. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  7. Dautigny A., Mattei M. G., Morello D., Alliel P. M., Pham-Dinh D., Amar L., Arnaud D., Simon D., Mattei J. F., Guenet J. L. The structural gene coding for myelin-associated proteolipid protein is mutated in jimpy mice. 1986 Jun 26-Jul 2Nature. 321(6073):867–869. doi: 10.1038/321867a0. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. 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]
  10. Gencic S., Hudson L. D. Conservative amino acid substitution in the myelin proteolipid protein of jimpymsd mice. J Neurosci. 1990 Jan;10(1):117–124. doi: 10.1523/JNEUROSCI.10-01-00117.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Hudson L. D., Puckett C., Berndt J., Chan J., Gencic S. Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8128–8131. doi: 10.1073/pnas.86.20.8128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kanfer J., Parenty M., Goujet-Zalc C., Monge M., Bernier L., Campagnoni A. T., Dautigny A., Zalc B. Developmental expression of myelin proteolipid, basic protein, and 2',3'-cyclic nucleotide 3'-phosphodiesterase transcripts in different rat brain regions. J Mol Neurosci. 1989;1(1):39–46. doi: 10.1007/BF02896855. [DOI] [PubMed] [Google Scholar]
  14. Knapp P. E., Skoff R. P., Redstone D. W. Oligodendroglial cell death in jimpy mice: an explanation for the myelin deficit. J Neurosci. 1986 Oct;6(10):2813–2822. doi: 10.1523/JNEUROSCI.06-10-02813.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. LeVine S. M., Wong D., Macklin W. B. Developmental expression of proteolipid protein and DM20 mRNAs and proteins in the rat brain. Dev Neurosci. 1990;12(4-5):235–250. doi: 10.1159/000111853. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. 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]
  20. Nadon N. L., Duncan I. D., Hudson L. D. A point mutation in the proteolipid protein gene of the 'shaking pup' interrupts oligodendrocyte development. Development. 1990 Oct;110(2):529–537. doi: 10.1242/dev.110.2.529. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. O'Dowd B. F., Hnatowich M., Caron M. G., Lefkowitz R. J., Bouvier M. Palmitoylation of the human beta 2-adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor. J Biol Chem. 1989 May 5;264(13):7564–7569. [PubMed] [Google Scholar]
  23. Ovchinnikov YuA, Abdulaev N. G., Bogachuk A. S. Two adjacent cysteine residues in the C-terminal cytoplasmic fragment of bovine rhodopsin are palmitylated. FEBS Lett. 1988 Mar 28;230(1-2):1–5. doi: 10.1016/0014-5793(88)80628-8. [DOI] [PubMed] [Google Scholar]
  24. Pham-Dinh D., Birling M. C., Roussel G., Dautigny A., Nussbaum J. L. Proteolipid DM-20 predominates over PLP in peripheral nervous system. Neuroreport. 1991 Feb;2(2):89–92. doi: 10.1097/00001756-199102000-00006. [DOI] [PubMed] [Google Scholar]
  25. Popot J. L., Pham Dinh D., Dautigny A. Major Myelin proteolipid: the 4-alpha-helix topology. J Membr Biol. 1991 Mar;120(3):233–246. doi: 10.1007/BF01868534. [DOI] [PubMed] [Google Scholar]
  26. Pratt V. M., Trofatter J. A., Schinzel A., Dlouhy S. R., Conneally P. M., Hodes M. E. A new mutation in the proteolipid protein (PLP) gene in a German family with Pelizaeus-Merzbacher disease. Am J Med Genet. 1991 Jan;38(1):136–139. doi: 10.1002/ajmg.1320380129. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Roussel G., Neskovic N. M., Trifilieff E., Artault J. C., Nussbaum J. L. Arrest of proteolipid transport through the Golgi apparatus in Jimpy brain. J Neurocytol. 1987 Apr;16(2):195–204. doi: 10.1007/BF01795303. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Shiota C., Ikenaka K., Mikoshiba K. Developmental expression of myelin protein genes in dysmyelinating mutant mice: analysis by nuclear run-off transcription assay, in situ hybridization, and immunohistochemistry. J Neurochem. 1991 Mar;56(3):818–826. doi: 10.1111/j.1471-4159.1991.tb01997.x. [DOI] [PubMed] [Google Scholar]
  31. Strittmatter S. M., Valenzuela D., Kennedy T. E., Neer E. J., Fishman M. C. G0 is a major growth cone protein subject to regulation by GAP-43. Nature. 1990 Apr 26;344(6269):836–841. doi: 10.1038/344836a0. [DOI] [PubMed] [Google Scholar]
  32. Trofatter J. A., Dlouhy S. R., DeMyer W., Conneally P. M., Hodes M. E. Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9427–9430. doi: 10.1073/pnas.86.23.9427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Verity A. N., Campagnoni A. T. Regional expression of myelin protein genes in the developing mouse brain: in situ hybridization studies. J Neurosci Res. 1988 Oct-Dec;21(2-4):238–248. doi: 10.1002/jnr.490210216. [DOI] [PubMed] [Google Scholar]
  34. Vermeesch M. K., Knapp P. E., Skoff R. P., Studzinski D. M., Benjamins J. A. Death of individual oligodendrocytes in jimpy brain precedes expression of proteolipid protein. Dev Neurosci. 1990;12(4-5):303–315. doi: 10.1159/000111859. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES