Skip to main content
SpringerLink
Log in

Pelizaeus–Merzbacher Disease and Spastic Paraplegia Type 2

  • Chapter
Genomic Disorders

  • 1047 Accesses

Abstract

Pelizaeus-Merzbacher disease (PMD) is a genomic disorder that is caused by altered dosage of a single gene, proteolipid protein 1 (itPLP1). Either duplication or deletion of itPLP1-containing genomic regions on chromosome Xq22.2 results in a severe leukodystrophy characterized by deficits of myelination in the central nervous system (itCNS). In this chapter, the molecular and genomic mechanisms for rearrangements causing PMD are reviewed, emphasizing differences in comparison to Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP)

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Lupski JR. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traitsTrends Genet 1998;14:417–422

    Article  PubMed  CAS  Google Scholar 

  2. Chance PF, Abbas N, Lensch MW, et al. Two autosomal dominant neuropathies result from reciprocal DNA duplication/deletion of a region on chromosome 17 Hum Mol Genet 1994;3:223–228

    Article  PubMed  CAS  Google Scholar 

  3. Ellis D, Malcolm S. Proteolipid protein gene dosage effect in Pelizaeus-Merzbacher disease Nat Genet 1994;6:333–334

    Article  PubMed  CAS  Google Scholar 

  4. Inoue K, Osaka H, Imaizumi K, et al. Proteolipid protein gene duplications causing Pelizaeus-Merzbacher disease: molecular mechanism and phenotypic manifestations Ann Neurol 1999;45:624–632

    Article  PubMed  CAS  Google Scholar 

  5. Inoue K, Osaka H, Sugiyama N, et al. A duplicated PLP gene causing Pelizaeus-Merzbacher disease detected by comparative multiplex PCR Am J Hum Genet 1996;59:32–39

    PubMed  CAS  Google Scholar 

  6. Inoue K, Osaka H, Thurston VC, et al. Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end-joining and cause different dysmyelinating phenotypes in males and females Am J Hum Genet 2002;71:838–853

    Article  PubMed  Google Scholar 

  7. Raskind WH, Williams CA, Hudson LD, Bird TD. Complete deletion of the proteolipid protein gene (PLP) in a family with X-linked Pelizaeus-Merzbacher disease Am J Hum Genet 1991;49:1355–1360

    PubMed  CAS  Google Scholar 

  8. Cremers FPM, Pfeiffer RA, van de Pol TJR, et al. An interstitial duplication of the X chromosome in a male allows physical fine mapping of probes from the Xq13-q22 region Human Genetics 1987;77:23–27

    Article  PubMed  CAS  Google Scholar 

  9. Woodward K, Kendall E, Vetrie D, Malcolm S. Pelizaeus-Merzbacher disease: identification of Xq22 proteolipid-protein duplications and characterization of breakpoints by interphase FISH Am J Hum Genet 1998;63:207–217

    Article  PubMed  CAS  Google Scholar 

  10. Hudson LD. Pelizaeus-Merzbacher disease and the allelic disorder X-linked spastic paraplegia type 2 In: The Metabolic and Molecular Bases of Inherited Diseases. 8th ed. (Scriver CR, Beaudet AL, Sly WS, Valle D, eds.), New York: McGraw-Hill, 2001; pp 5789–5798

    Google Scholar 

  11. Inoue K. PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2 Neurogenetics 2005;6:1–16

    Article  PubMed  CAS  Google Scholar 

  12. Hodes ME, Pratt VM, Dlouhy SR. Genetics of Pelizaeus-Merzbacher disease Dev Neurosci 1993;15:383–394

    PubMed  CAS  Google Scholar 

  13. Garbern J, Cambi F, Shy M, Kamholz J. The molecular pathogenesis of Pelizaeus-Merzbacher disease Arch Neurol 1999;56:1210–1214

    Article  PubMed  CAS  Google Scholar 

  14. Saugier-Veber P, Munnich A, Bonneau D, et al. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus Nat Genet 1994;6:257–262

    Article  PubMed  CAS  Google Scholar 

  15. Osaka H, Kawanishi C, Inoue K, et al. Novel nonsense proteolipid protein gene mutation as a cause of X-linked spastic paraplegia in twin males Biochem Biophys Res Commun 1995;215:835–841

    Article  PubMed  CAS  Google Scholar 

  16. Nave KA, Lai C, Bloom FE, Milner RJ. Splice site selection in the proteolipid protein (PLP) gene transcript and primary structure of the DM-20 protein of central nervous system myelin Proc Natl Acad Sci USA 1987;84:5665–5669

    Article  PubMed  CAS  Google Scholar 

  17. Maier M, Berger P, Nave KA, Suter U. Identification of the regulatory region of the peripheral myelin protein 22 (PMP22) gene that directs temporal and spatial expression in development and regeneration of peripheral nerves Mol Cell Neurosci 2002;20:93–109

    Article  PubMed  CAS  Google Scholar 

  18. Suter U, Snipes GJ, Schoener-Scott R, et al. Regulation of tissue-specific expression of alternative peripheral myelin protein-22 (PMP22) gene transcripts by two promoters J Biol Chem 1994;269:25,795-25,808.

    Google Scholar 

  19. Lupski JR, Garcia CA. Charcot-Marie-Tooth peripheral neuropathies and related disorders In: The Metabolic and Molecular Bases of Inherited Diseases 8th ed. (Scriver CR, Beaudet AL, Sly WS, Valle D, eds.), New York: McGraw-Hill, 2001; pp 5759–5788

    Google Scholar 

  20. Gow A, Lazzarini RA. A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease Nat Genet 1996;13:422–428

    Article  PubMed  CAS  Google Scholar 

  21. Gow A, Southwood CM, Lazzarini RA. Disrupted proteolipid protein trafficking results in oligodendrocyte apoptosis in an animal model of Pelizaeus-Merzbacher disease J Cell Biol 1998;140:925–934

    Article  PubMed  CAS  Google Scholar 

  22. D’Urso D, Prior R, Greiner-Petter R, Gabreëls-Festen AA, Müller HW. Overloaded endoplasmic reticulum-Golgi compartments, a possible pathomechanism of peripheral neuropathies caused by mutations of the peripheral myelin protein PMP22 J Neurosci 1998;18:731–740.

    PubMed  CAS  Google Scholar 

  23. Dickson KM, Bergeron JJ, Shames I, et al. Association of calnexin with mutant peripheral myelin protein-22 ex vivo: a basis for ‘gain-of-function’ ER diseases Proc Natl Acad Sci USA 2002;99:9852–9857

    Article  PubMed  CAS  Google Scholar 

  24. Swanton E, High S, Woodman P. Role of calnexin in the glycan-independent quality control of proteolipid protein EMBO J 2003;22:2948–2958

    Article  PubMed  CAS  Google Scholar 

  25. Southwood CM, Garbern J, Jiang W, Gow A. The unfolded protein response modulates disease severity in Pelizaeus-Merzbacher disease Neuron 2002;36:585–596

    Article  PubMed  CAS  Google Scholar 

  26. Lupski JR, Montes de Oca-Luna R, Slaugenhaupt S, et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A Cell 1991;66:219–232

    Article  PubMed  CAS  Google Scholar 

  27. LeGuern E, Gouider R, Mabin D, et al. Patients homozygous for the 17p11.2 duplication in Charcot-Marie-Tooth type 1A disease Ann Neurol 1997;41:104–108

    Article  PubMed  CAS  Google Scholar 

  28. Readhead C, Schneider A, Griffiths I, Nave KA. Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage Neuron 1994;12:583–595

    Article  PubMed  CAS  Google Scholar 

  29. Kagawa T, Ikenaka K, Inoue Y, et al. Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene Neuron 1994;13:427–442

    Article  PubMed  CAS  Google Scholar 

  30. Inoue Y, Kagawa T, Matsumura Y, Ikenaka K, Mikoshiba K. Cell death of oligodendrocytes or demyelination induced by overexpression of proteolipid protein depending on expressed gene dosage Neurosci Res 1996;25:161–172

    PubMed  CAS  Google Scholar 

  31. Anderson TJ, Schneider A, Barrie JA, et al. Late-onset neurodegeneration in mice with increased dosage of the proteolipid protein gene J Comp Neurol 1998;394:506–519

    Article  PubMed  CAS  Google Scholar 

  32. Huxley C, Passage E, Robertson AM, et al. Correlation between varying levels of PMP22 expression and the degree of demyelination and reduction in nerve conduction velocity in transgenic mice Hum Mol Genet 1998;7:449–458

    Article  PubMed  CAS  Google Scholar 

  33. Klugmann M, Schwab MH, Puhlhofer A, et al. Assembly of CNS myelin in the absence of proteolipid protein Neuron 1997;18:59–70

    Article  PubMed  CAS  Google Scholar 

  34. Griffiths I, Klugmann M, Anderson T, et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin Science 1998;280:1610–1613

    Article  PubMed  CAS  Google Scholar 

  35. Chance PF, Alderson MK, Leppig KA, et al. DNA deletion associated with hereditary neuropathy with liability to pressure palsies Cell 1993;72:143–151

    Article  PubMed  CAS  Google Scholar 

  36. Adlkofer K, Frei R, Neuberg DH, Zielasek J, Toyka KV, Suter U. Heterozygous peripheral myelin protein 22-deficient mice are affected by a progressive demyelinating tomaculous neuropathy J Neurosci 1997;17:4662–4671

    PubMed  CAS  Google Scholar 

  37. Adlkofer K, Martini R, Aguzzi A, Zielasek J, Toyka KV, and Suter U. Hypermyelination and demyelinating peripheral neuropathy in Pmp22-deficient mice Nat Genet 1995;11:274–280

    Article  PubMed  CAS  Google Scholar 

  38. Niemann S, Sereda MW, Suter U, Griffiths IR, Nave KA. Uncoupling of myelin assembly and schwann cell differentiation by transgenic overexpression of peripheral myelin protein 22 J Neurosci 2000;20:4120–4128

    PubMed  CAS  Google Scholar 

  39. Chies R, Nobbio L, Edomi P, Schenone A, Schneider C, Brancolini C. Alterations in the Arf6-regulated plasmamembrane endosomal recycling pathway in cells overexpressing the tetraspan protein Gas3/PMP22J Cell Sci 2003;116:987–999

    Article  PubMed  CAS  Google Scholar 

  40. Ryan MC, Shooter EM, Notterpek L. Aggresome formation in neuropathy models based on peripheral myelin protein 22 mutations Neurobiol Dis 2002];10:109–1

    Article  PubMed  CAS  Google Scholar 

  41. Simons M, Kramer EM, Macchi P, et al. Overexpression of the myelin proteolipid protein leads to accumulation of cholesterol and proteolipid protein in endosomes/lysosomes: implications for Pelizaeus-Merzbacher disease J Cell Biol 2002;157:327–336

    Article  PubMed  CAS  Google Scholar 

  42. Simons M, Kramer EM, Thiele C, Stoffel W, Trotter J. Assembly of myelin by association of proteolipid protein with cholesterol-and galactosylceramide-rich membrane domains J Cell Biol 2000;151:143–154

    Article  PubMed  CAS  Google Scholar 

  43. Inoue K, Kanai M, Tanabe Y, et al. Prenatal interphase FISH diagnosis of PLP1 duplication associated with Pelizaeus-Merzbacher disease Prenat Diagn 2001211133–1136

    Article  PubMed  CAS  Google Scholar 

  44. Hodes ME, Woodward K, Spinner NB, et al. Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosomeAm J Hum Genet 2000;67:14–22

    Article  PubMed  CAS  Google Scholar 

  45. Regis S, Filocamo M, Mazzotti R, et al. Prenatal diagnosis of Pelizaeus-Merzbacher disease: detection of proteolipid protein gene duplication by quantitative fluorescent multiplex PCR Prenat Diagn 2001;21:668–671

    Article  PubMed  CAS  Google Scholar 

  46. Mimault C, Giraud G, Courtois V, et al. and The Clinical European Network on Brain Dysmyelinating Disease Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not Am J Hum Genet 1999;65:360–369

    PubMed  CAS  Google Scholar 

  47. Shaw CJ, Shaw CA, Yu W, et al. [atComparative genomic hybridisation using a proximal 17p BAC/PAC array detects rearrangements responsible for four genomic disorders J Med Genet 2004;41:113–119

    Article  PubMed  CAS  Google Scholar 

  48. Albertson DG, Pinkel D. Genomic microarrays in human genetic disease and cancer Hum Mol Genet 2003;12:R145–R152

    Article  PubMed  CAS  Google Scholar 

  49. Mantripragada KK, Buckley PG, de Stahl TD, Dumanski JP. Genomic microarrays in the spotlight Trends Genet 2004;20:87–94

    Article  PubMed  CAS  Google Scholar 

  50. Inoue K, Lupski JR. Molecular mechanisms for genomic disorders Annu Rev Genomics Hum Genet2002;3:199–242

    Article  PubMed  CAS  Google Scholar 

  51. Pentao L, Wise CA, Chinault AC, Patel PI, Lupski JR. Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit Nat Genet 1992;2:292–300

    Article  PubMed  CAS  Google Scholar 

  52. Inoue K, Dewar K, Katsanis N, et al. The 1.4-Mb CMT1A duplication/HNPP deletion genomic region reveals unique genome architectural features and provides insights into the recent evolution of new genesGenome Res 2001;11:1018–1033.

    Article  PubMed  CAS  Google Scholar 

  53. Stankiewicz P, Lupski JR. Genome architecture, rearrangements and genomic disorders Trends Genet 2002;18:74–82

    Article  PubMed  CAS  Google Scholar 

  54. Lee J, Dean M, Gold B, Inoue K, Lupski JR. Role of genomic architecture in PLP1 duplication causing Pelizaeus-Merzbacher disease American Society of Human Genetics, 54th Annual Meeting Toronto, 2004; pp A103

    Google Scholar 

  55. Hobson G, Cundall M, Sperle K, et al. Fine mapping of duplication endpoints in Pelizaeus-Merzbacher disease American Society of Human Genetics, 53rd Annual Meeting Los Angels, 2003; pp A1009

    Google Scholar 

  56. Iwaki A, Kondo J, Ototsuji M, Kurosawa K, Fukumaki Y. Characterization of the breakpoints of PLP1 duplication in three cases of Pelizaeus-Merzbacher disease American Society of Human Genetics, 53rd Annual Meeting Los Angels, 2003; pp A2229

    Google Scholar 

  57. Shaw CJ, Lupski JR. Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease Hum Mol Genet 2004;13:R57–R64

    Article  PubMed  CAS  Google Scholar 

  58. Heim P, Claussen M, Hoffmann B, et al. Leukodystrophy incidence in Germany Am J Med Genet 1997;71:475–478

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. National Institute of Neuroscience, National Center of Neurology, Department of Mental Retardation and Birth Defect Research, Kodaira, Tokyo, Japan

    Ken Inoue PhD, MD

Authors
  1. Ken Inoue PhD, MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

    James R. Lupski MD, PhD  & Pawel Stankiewicz MD, PhD  & 

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Inoue, K. (2006). Pelizaeus–Merzbacher Disease and Spastic Paraplegia Type 2. In: Lupski, J.R., Stankiewicz, P. (eds) Genomic Disorders. Humana Press. https://doi.org/10.1007/978-1-59745-039-3_18

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-039-3_18

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-559-0

  • Online ISBN: 978-1-59745-039-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation