Hostname: page-component-8448b6f56d-wq2xx Total loading time: 0 Render date: 2024-04-19T00:24:03.104Z Has data issue: false hasContentIssue false
  • English
  • Français

The molecular and cellular defects underlying Pelizaeus–Merzbacher disease

Published online by Cambridge University Press:  19 May 2008

Karen J. Woodward
Karen J. Woodward
Affiliation:
Western Diagnostic Pathology, 74 McCoy Street, Myaree, WA 6154, Australia. Tel: +61 8 317 0999; Fax: +61 8 317 0777; E-mail: Karen.Woodward@symbionhealth.com
Get access Rights & Permissions [Opens in a new window]

Abstract

Pelizaeus–Merzbacher disease (PMD) is a recessive X-linked dysmyelinating disorder of the central nervous system (CNS). The most frequent cause of PMD is a genomic duplication of chromosome Xq22 including the region encoding the dosage-sensitive proteolipid protein 1 (PLP1) gene. The PLP1 duplications are heterogeneous in size, unlike duplications causing many other genomic disorders, and arise by a distinct molecular mechanism. Other causes of PMD include PLP1 deletions, triplications and point mutations. Mutations in the PLP1 gene can also give rise to spastic paraplegia type 2 (SPG2), an allelic form of the disease. Thus, there is a spectrum of CNS disorder from mild SPG2 to severe connatal PMD. PLP1 encodes a major protein in CNS myelin and is abundantly expressed in oligodendrocytes, the myelinating cells of the CNS. Significant advances in our understanding of PMD have been achieved by investigating mutant PLP1 in PMD patients, animal models and in vitro studies. How the different PLP1 mutations and dosage effects give rise to PMD is being revealed. Interestingly, the underlying causes of pathogenesis are distinct for each of the different genetic abnormalities. This article reviews the genetics of PMD and summarises the current knowledge of causative molecular and cellular mechanisms.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 10 , October 2008 , e14
Copyright
Copyright © Cambridge University Press 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Heim, P. et al. (1997) Leukodystrophy incidence in Germany. Am J Med Genet 71, 475-4783.0.CO;2-C>CrossRefGoogle ScholarPubMed
2Pelizaeus, F. (1885) Über eine eigenthümliche Form Spastischer Lähmung mit Cerebralerschinungen auf hereditärer Grundlage (Multiple Sklerose). Arch Psychiatr Nervenkr 16, 698-710CrossRefGoogle Scholar
3Merzbacher, L. (1910) Eine eigenarige familiär-hereditare Erkrankungsform (Aplasia axialis extra-corticalis congenita). Z ges Neurol Psych 3, 1-138CrossRefGoogle Scholar
4Dautigny, A. et al. (1986) The structural gene coding for myelin-associated proteolipid protein is mutated in jimpy mice. Nature 321, 867-869CrossRefGoogle ScholarPubMed
5Nave, K.A. et al. (1986) 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 83, 9264-9268CrossRefGoogle Scholar
6Hudson, L.D. et al. (1987) Aberrant splicing of proteolipid protein mRNA in the dysmyelinating jimpy mutant mouse. Proc Natl Acad Sci U S A. 84, 1454-1458CrossRefGoogle ScholarPubMed
7Boison, D. and Stoffel, W. (1989) 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 8, 3295-3302CrossRefGoogle Scholar
8Mattei, M.G. et al. (1986) The gene encoding for the major brain proteolipid (PLP1) maps on the q-22 band of the human X chromosome. Hum Genet 72, 352-353CrossRefGoogle Scholar
9Hudson, L.D. et al. (1989) Mutation of the proteolipid protein gene PLP1 in a human X chromosome-linked myelin disorder. Proc Natl Acad Sci U S A 86, 8128-8131CrossRefGoogle Scholar
10Gencic, S. et al. (1989) 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 45, 435-442Google ScholarPubMed
11Trofatter, J.A. et al. (1989) Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant. Proc Natl Acad Sci U S A 86, 9427-9430CrossRefGoogle ScholarPubMed
12Saugier-Veber, P. et al. (1994) X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet 6, 257-262CrossRefGoogle ScholarPubMed
13Boespflug-Tanguy, O. et al. (1994) Genetic homogeneity of Pelizaeus-Merzbacher disease: tight linkage to the proteolipoprotein locus in 16 affected families. Am J Hum Genet 55, 461-467Google Scholar
14Lupski, J.R. and Garcia, C.A. (1992) Molecular genetics and neuropathology of Charcot-Marie-Tooth disease type 1A. Brain Pathol 2, 337-349CrossRefGoogle ScholarPubMed
15Ellis, D. and Malcolm, S. (1994) Proteolipid protein gene dosage effect in Pelizaeus-Merzbacher disease. Nat.Genet 6, 333-334CrossRefGoogle ScholarPubMed
16Sistermans, E.A. et al. (1998) Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease. Neurology 50, 1749-1754CrossRefGoogle ScholarPubMed
17Inoue, K. et al. (1996) A duplicated PLP1 gene causing Pelizaeus-Merzbacher disease detected by comparative multiplex PCR. Am J Hum Genet 59, 32-39Google Scholar
18Wang, P.J. et al. (1997) Duplication of proteolipid protein gene: a possible major cause of Pelizaeus-Merzbacher disease. Pediatr Neurol 17, 125-128CrossRefGoogle ScholarPubMed
19Raskind, W.H. et al. (1991) Complete deletion of the proteolipid protein gene (PLP1) in a family with X-linked Pelizaeus-Merzbacher disease. Am J Hum Genet 49, 1355-1360Google Scholar
20Inoue, K. et al. (2002) Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females. Am J Hum Genet 71, 838-853CrossRefGoogle ScholarPubMed
21Lazzarini, R. (2004) Myelin biology and disorders, ElsevierGoogle Scholar
22Griffiths, I. et al. (1998) Current concepts of PLP1 and its role in the nervous system. Microsc Res Tech 41, 344-3583.0.CO;2-Q>CrossRefGoogle ScholarPubMed
23Yool, D.A. et al. (2000) The proteolipid protein gene and myelin disorders in man and animal models. Hum Mol Genet 9, 987-992CrossRefGoogle ScholarPubMed
24Readhead, C. et al. (1994) Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage. Neuron 12, 583-595CrossRefGoogle ScholarPubMed
25Kagawa, T. et al. (1994) Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene. Neuron 13, 427-442CrossRefGoogle ScholarPubMed
26Inoue, Y. et al. (1996) Cell death of oligodendrocytes or demyelination induced by overexpression of proteolipid protein depending on expressed gene dosage. Neurosci Res 25, 161-172CrossRefGoogle ScholarPubMed
27Boison, D. and Stoffel, W. (1994) Disruption of the compacted myelin sheath of axons of the central nervous system in proteolipid protein-deficient mice. Proc Natl Acad Sci USA 91, 11709-11713CrossRefGoogle ScholarPubMed
28Klugmann, M. et al. (1997) Assembly of CNS myelin in the absence of proteolipid protein. Neuron 18, 59-70CrossRefGoogle ScholarPubMed
29Stecca, B. et al. (2000) The evolution of lipophilin genes from invertebrates to tetrapods: DM-20 cannot replace proteolipid protein in CNS myelin. J Neurosci. 20, 4002-4010CrossRefGoogle ScholarPubMed
30Steitelberger, F. (1970) Pelizaeus-Merzbacher disease. Handb Clin Neurol 10, 150-220Google Scholar
31Seitelberger, F. (1995) Neuropathology and genetics of Pelizaeus-Merzbacher disease. Brain Pathol 5, 267-273CrossRefGoogle ScholarPubMed
32Cailloux, F. et al. (2000) Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Eur J Hum Genet 8, 837-845CrossRefGoogle ScholarPubMed
33Boulloche, J. and Aicardi, J. (1986) Pelizaeus-Merzbacher disease: clinical and nosological study. J Child Neurol 1, 233-239CrossRefGoogle ScholarPubMed
34Hodes, M.E., Pratt, V.M., Dlouhy, S.R. (1993) Genetics of Pelizaeus-Merzbacher disease. Dev Neurosci 15, 383-394CrossRefGoogle ScholarPubMed
35Inoue, K. (2005) PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 6, 1-16CrossRefGoogle ScholarPubMed
36Garbern, J.Y. (2007) Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis. Cell Mol Life Sci 64, 50-65CrossRefGoogle ScholarPubMed
37Scheffer, I.E. et al. (1991) Pelizaeus-Merzbacher disease: classical or connatal? Neuropediatrics 22, 71-78CrossRefGoogle ScholarPubMed
38Diehl, H.J. et al. (1986) Individual exons encode the integral membrane domains of human myelin proteolipid protein. Proc Natl Acad Sci USA 83, 9807-9811CrossRefGoogle ScholarPubMed
39Nave, K.A. et al. (1987) Splice site selection in the proteolipid protein (PLP1) gene transcript and primary structure of the DM-20 protein of central nervous system myelin. Proc Natl Acad Sci USA 84, 5665-5669CrossRefGoogle ScholarPubMed
40Eng, L.F. et al. (1968) The maturation of human white matter myelin. Fractionation of the myelin membrane proteins. Biochemistry 7, 4455-4465Google ScholarPubMed
41Lees, M. and Brostoff, S.L. (1984) Proteins of myelin. In Myelin (Vol 2) (Morell, P. ed.), pp. 197-224, New York, PlenumCrossRefGoogle Scholar
42Popot, J.L., Pham Dinh, D. and Dautigny, A. (1991) Major Myelin proteolipid: the 4-alpha-helix topology. J Membr Biol 120, 233-246CrossRefGoogle ScholarPubMed
43Weimbs, T. and Stoffel, W. (1992) Proteolipid protein (PLP1) of CNS myelin: positions of free, disulfide-bonded, and fatty acid thioester-linked cysteine residues and implications for the membrane topology of PLP1. Biochemistry 31, 12289-12296CrossRefGoogle Scholar
44Gow, A. et al. (1997) Conservation of topology, but not conformation, of the proteolipid proteins of the myelin sheath. J Neurosci 17, 181-189CrossRefGoogle Scholar
45Milner, R.J. et al. (1985) Nucleotide sequences of two mRNAs for rat brain myelin proteolipid protein. Cell 42, 931-939CrossRefGoogle ScholarPubMed
46Campagnoni, A.T. and Skoff, R.P. (2001) The pathobiology of myelin mutants reveal novel biological functions of the MBP and PLP1 genes. Brain Pathol 11, 74-91CrossRefGoogle Scholar
47Campagnoni, C.W. et al. (1992) DM20 mRNA splice product of the myelin proteolipid protein gene is expressed in the murine heart. J Neurosci Res 33, 148-155CrossRefGoogle ScholarPubMed
48Pribyl, T.M. et al. The major myelin protein genes are expressed in the human thymus. J Neurosci Res 45, 812-8193.0.CO;2-X>CrossRefGoogle Scholar
49Nussbaum, J.L. and Roussel, G. (1983) Immunocytochemical demonstration of the transport of myelin proteolipids through the Golgi apparatus. Cell Tissue Res 234, 547-559CrossRefGoogle ScholarPubMed
50Simons, M. et al. (2000) Assembly of myelin by association of proteolipid protein with cholesterol and galactosylceramide-rich membrane domains. J Cell Biol 151, 143-154CrossRefGoogle ScholarPubMed
51Simons, M. et al. (2002) 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 157, 327-336CrossRefGoogle ScholarPubMed
52Klugmann, M. et al. (1997) Assembly of CNS myelin in the absence of proteolipid protein. Neuron 18, 59-70CrossRefGoogle ScholarPubMed
53Bizzozero, O.A. et al. (2001) Chemical deacylation reduces the adhesive properties of proteolipid protein and leads to decompaction of the myelin sheath. J Neurochem 76, 1129-1141CrossRefGoogle ScholarPubMed
54Knapp, P.E. (1996) Proteolipid protein: is it more than just a structural component of myelin? Dev Neurosci 18, 297-308CrossRefGoogle ScholarPubMed
55Kitagawa, K. et al. (1993) A proteolipid protein gene family: expression in sharks and rays and possible evolution from an ancestral gene encoding a pore-forming polypeptide. Neuron 11, 433-448CrossRefGoogle ScholarPubMed
56Gudz, T.I. et al. (2002) Myelin proteolipid protein forms a complex with integrins and may participate in integrin receptor signaling in oligodendrocytes. J Neurosci 22, 7398-7407CrossRefGoogle ScholarPubMed
57Spörkel, O. et al. (2002) Oligodendrocytes expressing exclusively the DM20 isoform of the proteolipid protein gene: myelination and development. Glia 37, 19-30CrossRefGoogle ScholarPubMed
58Woodward, K. et al. (1998) Pelizaeus-Merzbacher disease: identification of Xq22 proteolipid-protein duplications and characterization of breakpoints by interphase FISH. Am J Hum Genet 63, 207-217CrossRefGoogle ScholarPubMed
59Inoue, K. et al. (1999) Proteolipid protein gene duplications causing Pelizaeus-Merzbacher disease: molecular mechanism and phenotypic manifestations. Ann Neurol 45, 624-6323.0.CO;2-1>CrossRefGoogle ScholarPubMed
60Woodward, K.J. et al. (2005) Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination. Am J Hum Genet 77, 966-987CrossRefGoogle ScholarPubMed
61Mimault, C. et al. (1999) 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 65, 360-369CrossRefGoogle ScholarPubMed
62Wolf, N.I. et al. (2005) Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease. Brain 128, 743-751CrossRefGoogle ScholarPubMed
63Hodes, M.E. et al. (2000) Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome. Am J Hum Genet 67, 14-22CrossRefGoogle ScholarPubMed
64Woodward, K. et al. (2003) Complex chromosomal rearrangement and associated counseling issues in a family with Pelizaeus-Merzbacher disease. Am J Med Genet A 118, 15-24CrossRefGoogle Scholar
65Lupski, J.R. (1998) Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet 14, 417-422CrossRefGoogle ScholarPubMed
66Inoue, K. and Lupski, J.R. (2002) Molecular mechanisms for genomic disorders. Annu Rev Genomics Hum Genet 3, 199-242CrossRefGoogle ScholarPubMed
67Lee, J.A. et al. (2006) Role of genomic architecture in PLP1 duplication causing Pelizaeus-Merzbacher disease. Hum Mol Genet 15, 2250-2265CrossRefGoogle ScholarPubMed
68Lee, J.A., Carvalho, C.M. and Lupski, J.R. (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235-1247CrossRefGoogle ScholarPubMed
69Shaw, C.J. and Lupski, J.R. (2004) Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum Mol Genet 13, 57-64CrossRefGoogle ScholarPubMed
70Regis, S. et al. (2001) Prenatal diagnosis of Pelizaeus-Merzbacher disease: detection of proteolipid protein gene duplication by quantitative fluorescent multiplex PCR. Prenat Diagn 21, 668-671CrossRefGoogle ScholarPubMed
71Hübner, C.A. et al. (2005) Seventeen novel PLP1 mutations in patients with Pelizaeus-Merzbacher disease. Hum Mutat 25, 321-322CrossRefGoogle ScholarPubMed
72Gao, Q. et al. (2005) Genetic diagnosis of PLP1 gene duplications/deletions in patients with Pelizaeus-Merzbacher disease. Clin Genet 68, 466-467CrossRefGoogle Scholar
73Mikesová, E. et al. (2006) Quantitative multiplex real-time PCR for detection of PLP1 gene duplications in Pelizaeus-Merzbacher patients. Genet Test 10, 215-220CrossRefGoogle ScholarPubMed
74Warshawsky, I. et al. (2006) Multiplex ligation-dependent probe amplification for rapid detection of proteolipid protein 1 gene duplications and deletions in affected males and carrier females with Pelizaeus-Merzbacher disease. Clin Chem 52, 1267-1275CrossRefGoogle ScholarPubMed
75Woodward, K. et al. (1999) Prenatal diagnosis by FISH in a family with Pelizaeus-Merzbacher disease caused by duplication of PLP1 gene. Prenat Diagn 19, 266-2683.0.CO;2-#>CrossRefGoogle Scholar
76Lee, J.A. et al. (2005) Prenatal diagnosis of PLP1 copy number by array comparative genomic hybridization. Prenat Diagn 25, 1188-1191CrossRefGoogle ScholarPubMed
77Verlinsky, Y. et al. (2006) Preimplantation genetic diagnosis for Pelizaeus-Merzbacher disease with testing for age-related aneuploidies. Reprod Biomed Online 12, 83-88CrossRefGoogle ScholarPubMed
78Sistermans, E.A. et al. (1996) A (G-to-A) mutation in the initiation codon of the proteolipid protein gene causing a relatively mild form of Pelizaeus-Merzbacher disease in a Dutch family. Hum Genet 97, 337-339CrossRefGoogle Scholar
79Garbern, J.Y. et al. (1997) Proteolipid protein is necessary in peripheral as well as central myelin. Neuron 19, 205-218CrossRefGoogle ScholarPubMed
80Garbern, J.Y. et al. (2002) Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 125, 551-561CrossRefGoogle ScholarPubMed
81Hobson, G.M. et al. (2000) Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease. Neurology 55, 1089-1096CrossRefGoogle ScholarPubMed
82Hobson, G.M. et al. (2006) Splice-site contribution in alternative splicing of PLP1 and DM20: molecular studies in oligodendrocytes. Hum Mutat 27, 69-77CrossRefGoogle ScholarPubMed
83Nave, K.A. and Lemke, G. (1991) Induction of the myelin proteolipid protein (PLP1) gene in C6 glioblastoma cells: functional analysis of the PLP1 promotor. J Neurosci 11, 3060-3069CrossRefGoogle Scholar
84Berndt, J.A., Kim, J.G. and Hudson, L.D. (1992) Identification of cis-regulatory elements in the myelin proteolipid protein (PLP1) gene. J Biol Chem 267, 14730-14737CrossRefGoogle Scholar
85Dobretsova, A., Kokorina, N.A. and Wight, P.A. (2004) Potentiation of myelin proteolipid protein (PLP1) gene expression is mediated through AP-1-like binding sites. J Neurochem 90, 1500-1510CrossRefGoogle Scholar
86Bongarzone, E.R. et al. (1999) Identification of a new exon in the myelin proteolipid protein gene encoding novel protein isoforms that are restricted to the somata of oligodendrocytes and neurons. J Neurosci 19, 8349-8357CrossRefGoogle Scholar
87Muncke, N. et al. (2004) Position effect on PLP1 may cause a subset of Pelizaeus-Merzbacher disease symptoms. J Med Genet 41, e121CrossRefGoogle Scholar
88Lee, J.A. et al. (2006) Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann Neurol 59, 398-403CrossRefGoogle ScholarPubMed
89Uhlenberg, B. et al. (2004) Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am J Hum Genet 75, 251-260CrossRefGoogle ScholarPubMed
90Wolf, N.I. et al. (2007) Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination. Neurogenetics 8, 39-44CrossRefGoogle ScholarPubMed
91Bugiani, M. et al. (2006) GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy. Neurology 67, 273-279CrossRefGoogle ScholarPubMed
92Salviati, L. et al. (2007) A novel deletion in the GJA12 gene causes Pelizaeus-Merzbacher-like disease. Neurogenetics 8, 57-60CrossRefGoogle ScholarPubMed
93Orthmann-Murphy, J.L. et al. (2007) Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease. Mol Cell Neurosci 34, 629-641CrossRefGoogle ScholarPubMed
94Bergoffen, J. et al. (1993) Linkage localization of X-linked Charcot-Marie-Tooth disease. Am J Hum Genet 52, 312-318Google ScholarPubMed
95Menichella, D.M. et al. (2003) Connexins are critical for normal myelination in the CNS. J Neurosci 23, 5963-5973CrossRefGoogle ScholarPubMed
96Odermatt, B. et al. (2003) Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS. J Neurosci 23, 4549-4559CrossRefGoogle ScholarPubMed
97Nave, K.A. and Boespflug-Tanguy, O. (1996) X-linked developmental defects of myelination: from mouse mutants to human genetic diseases. Neuroscientist 2, 33-43CrossRefGoogle Scholar
98Inoue, K. et al. (2004) Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat Genet 36, 361-369CrossRefGoogle ScholarPubMed
99Al-Saktawi, K. et al. (2003) Genetic background determines phenotypic severity of the PLP1 rumpshaker mutation. J Neurosci Res 72, 12-24CrossRefGoogle Scholar
100Schneider, A.M. et al. (1992) Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene. Nature 358, 758-761CrossRefGoogle ScholarPubMed
101Anderson, T.J. et al. (1998) Late-onset neurodegeneration in mice with increased dosage of the proteolipid protein gene. J Comp Neurol 394, 506-5193.0.CO;2-5>CrossRefGoogle ScholarPubMed
102Karim, S.A. et al. (2007) PLP1 overexpression perturbs myelin protein composition and myelination in a mouse model of Pelizaeus-Merzbacher disease. Glia 55, 341-351CrossRefGoogle Scholar
103Sereda, M. et al. (1996) A transgenic rat model of Charcot-Marie-Tooth disease. Neuron 16, 1049-1060CrossRefGoogle ScholarPubMed
104Griffiths, I. et al. (1998) Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280, 1610-1613CrossRefGoogle ScholarPubMed
105Garbern, J.Y. et al. (1999) Peripheral neuropathy caused by proteolipid protein gene mutations. Ann N Y Acad Sci 883, 351-365CrossRefGoogle ScholarPubMed
106Roussel, G. et al. (2003) Arrest of proteolipid transport through the Golgi apparatus in Jimpy brain. J Neurocytol 16, 195-204CrossRefGoogle Scholar
107Gow, A., Friedrich, V.-L.J. and Lazzarini, R.A. (1994) Intracellular transport and sorting of the oligodendrocyte transmembrane proteolipid protein. J Neurosci Res 37, 563-573CrossRefGoogle ScholarPubMed
108Gow, A. and Lazzarini, R.A. (1996) A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease. Nat Genet 13, 422-428CrossRefGoogle ScholarPubMed
109Thomson, C.E. et al. (1997) Phenotypic severity of murine PLP1 mutants reflects in vivo and in vitro variations in transport of PLP1 isoproteins. Glia 20, 322-3323.0.CO;2-7>CrossRefGoogle Scholar
110Gow, A., Southwood, C.M. and Lazzarini, R.A. (1998) Disrupted proteolipid protein trafficking results in oligodendrocyte apoptosis in an animal model of Pelizaeus-Merzbacher disease. J Cell Biol 140, 925-934CrossRefGoogle Scholar
111Cerghet, M. et al. (2001) Differential expression of apoptotic markers in jimpy and in PLP1 overexpressors: evidence for different apoptotic pathways. J Neurocytol 30, 841-855CrossRefGoogle Scholar
112Southwood, C.M. et al. (2002) The unfolded protein response modulates disease severity in Pelizaeus-Merzbacher disease. Neuron 36, 585-596CrossRefGoogle ScholarPubMed
113Schneider, A.M. et al. (1995) Dominant-negative action of the jimpy mutation in mice complemented with an autosomal transgene for myelin proteolipid protein. Proc Natl Acad Sci U S A 92, 4447-4451CrossRefGoogle ScholarPubMed
114Taylor, J.P. et al. (2002) Toxic proteins in neurodegenerative disease. Science 296, 1991-1995CrossRefGoogle ScholarPubMed
115Hoozemans, J.J. et al. (2005) The unfolded protein response is activated in Alzheimer's disease. Acta Neuropathol 110, 165-172CrossRefGoogle ScholarPubMed
116Hoozemans, J.J. et al. (2007) Activation of the unfolded protein response in Parkinson's disease. Biochem Biophys Res Commun 354, 707-711CrossRefGoogle ScholarPubMed
117Krämer-Albers, E.M. et al. (2007) Perturbed interactions of mutant proteolipid protein/DM20 with cholesterol and lipid rafts in oligodendroglia: implications for dysmyelination in spastic paraplegia. J Neurosci 26, 11743-11752CrossRefGoogle Scholar
118McLaughlin, M. et al. (2006) Processing of PLP in a model of Pelizaeus-Merzbacher disease/SPG2 due to the rumpshaker mutation. Glia 53, 715-722CrossRefGoogle Scholar
119McLaughlin, M. et al. (2007) Genetic background influences UPR but not PLP1 processing in the rumpshaker model of PMD/SPG2. Neurochem Res 32, 167-176CrossRefGoogle Scholar
120Swanton, E. et al. (2005) Disease-associated mutations cause premature oligomerization of myelin proteolipid protein in the endoplasmic reticulum. Proc Natl Acad Sci U S A 102, 4342-4347CrossRefGoogle ScholarPubMed
121Dhaunchak, A.S. and Nave, K.A. (2007) A common mechanism of PLP1/DM20 misfolding causes cysteine-mediated endoplasmic reticulum retention in oligodendrocytes and Pelizaeus-Merzbacher disease. Proc Natl Acad Sci USA 104, 17813-17818CrossRefGoogle Scholar
122Southwood, C. et al. (2007) Novel alternatively spliced endoplasmic reticulum retention signal in the cytoplasmic loop of Proteolipid Protein-1. J Neurosci Res 85, 471-478CrossRefGoogle ScholarPubMed
123Nance, M.A. et al. (1996) Adult-onset neurodegenerative disorder due to proteolipid protein gene mutation in the mother of a man with Pelizaeus-Merzbacher disease. Neurology 47, 1333-1335CrossRefGoogle Scholar
124Hodes, M.E. et al. (1997) Nonsense mutation in exon 3 of the proteolipid protein gene (PLP1) in a family with an unusual form of Pelizaeus-Merzbacher disease. Am J Med Genet 69, 121-1253.0.CO;2-S>CrossRefGoogle Scholar
125Sivakumar, K. et al. (1999) Novel exon 3B proteolipid protein gene mutation causing late-onset spastic paraplegia type 2 with variable penetrance in female family members. Ann Neurol 45, 680-6833.0.CO;2-H>CrossRefGoogle ScholarPubMed
126Hurst, S. et al. (2006) Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease. Genet Med 8, 371-378CrossRefGoogle ScholarPubMed
127Fanarraga, M.L. (1991) Rumpshaker: an X-linked mutation affecting CNS myelination. A study of the female heterozygote. Neuropathol Appl Neurobiol 17, 323-334CrossRefGoogle ScholarPubMed
128Woodward, K. et al. (2000) X inactivation phenotype in carriers of Pelizaeus-Merzbacher disease: skewed in carriers of a duplication and random in carriers of point mutations. Eur J Hum Genet 8, 449-454CrossRefGoogle ScholarPubMed
129Inoue, K. et al. (2001) Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement. Ann Neurol 50, 747-754CrossRefGoogle ScholarPubMed
130Marble, M. (2007) Pelizaeus-Merzbacher syndrome: neurocognitive function in a family with carrier manifestations. Am J Med Genet A 143, 1442-1447CrossRefGoogle Scholar
131Duncan, I.D., Grever, W.E. and Zhang, S.C. (1997) Repair of myelin disease: strategies and progress in animal models. Mol Med Today 3, 554-561CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

The Online Mendelian Inheritance in Man (OMIM) website provides an overview of Pelizaeus–Merzbacher disease and references to the most significant publications.

www.ncbi.nlm.nih.gov/omimGoogle Scholar
www.genetests.orgGoogle Scholar
www.pmdfoundation.orgGoogle Scholar
www.ncbi.nlm.nih.gov/omimGoogle Scholar
www.genetests.orgGoogle Scholar
www.pmdfoundation.orgGoogle Scholar