Elevated expression of messenger RNA for peripheral myelin protein 22 in biopsied peripheral nerves of patients with Charcot‐Marie‐Tooth disease type 1A

Yoshikawa, Hiroaki; Nishimura, Tomoya; Nakatsuji, Yuji; Fujimura, Harutoshi; Himoro, Masato; Hayasaka, Kiyoshi; Sakoda, Saburo; Yanagihara, Takehiko

doi:10.1002/ana.410350412

Cited by 132 publications

(47 citation statements)

References 29 publications

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“…These data, together with the evidence that the PMP22 gene is not disrupted within the tandem DNA duplication, support the hypothesis of a gene dosage mechanism as a cause of the pathogenesis of CMT 1A and HNPP. However, it has also been reported that the levels of PMP22 mRNA expression change with the progression of the disease (Hanemann et al, 1994;Yoshikawa et al, 1994). Thus the pathogenetic cascade of events seems to be more complex than initially anticipated.…”

Section: Introductionmentioning

confidence: 87%

Studies on the effects of altered PMP22 expression during myelination in vitro

et al. 1997

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Section: Introductionmentioning

confidence: 87%

Studies on the effects of altered PMP22 expression during myelination in vitro

et al. 1997

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“…In humans, a large proportion of patients with CMT and hereditary neuropathy with liability to pressure palsies are caused by altered PMP22 gene dosage resulting from a duplication or deletion, respectively, of a submicroscopic portion of chromosome 17 containing the human PMP22 gene (see Suter and Snipes, 1995a). Although controversial, the altered PMP22 gene dosage in CMT1A appears to be reflected by increased levels of PMP22 mRNA in Schwann cells (Yoshikawa, 1994) and PMP22 protein in peripheral myelin (Vallat, 1996; see also Hanemann, 1994). In mouse models alone, altered dosage of normal myelin genes causing myelination defects has now been described for the major compact myelin proteins in both the CNS and PNS, namely for MBP (Shine et al, 1992), P0 (Giese et al, 1992;Martini et al, 1995), PLP (Nave, 1994), and PMP22 (Adlkofer et al, 1996;Magyar et al, 1996;Sereda et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of the Endosomal-Lysosomal Pathway in the Trembler-J Neuropathy

1997

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A nonconservative leucine to proline mutation in peripheral myelin protein 22 (PMP22) causes the Trembler-J (Tr J ) neuropathy in mice and humans. The expression levels and localization of the PMP22 protein in the Tr J mouse have not been previously determined. The aim of our studies was to reevaluate the extent of myelin deficit in genotyped heterozygous and homozygous animals and to examine how the Tr J mutation alters the normal in vivo post-translational processing of PMP22. Morphological studies show evidence for primary dysmyelination and myelin instability in affected animals. As expected, Western blot analysis indicates that in adult heterozygous Tr J animals, the level of PMP22 is markedly decreased, similar to myelin basic protein and protein zero, whereas myelin-associated glycoprotein is largely unaffected. The decrease in myelin protein expression is associated with an increase in lysosomal biogenesis, suggestive of augmented endocytosis or autophagy. Double-immunolabeling experiments show the accumulation of PMP22 in endosomal/lysosomal structures of Tr J Schwann cells, and chloroquine treatment of nerve segments indicates that the degradation of protein zero, PMP22, and myelin basic protein is augmented in Tr J nerves. These studies suggest that the Tr J mutation alters myelin stability and that the mutant protein is likely degraded via the lysosomal pathway. Key words: peripheral myelin protein 22; Schwann cells; peripheral nervous system; myelin; neuropathy; Trembler-J; endosomal-lysosomal pathway; protein processingThe Trembler (Tr) and Trembler-J (Tr J ) mice are animal models for the human hereditary neuropathy Charcot-Marie-Tooth (CMT) disease, a group of common (1/2500) (Skre, 1974) heterogeneous peripheral neuropathies. In mice, the semidominant and dominantly inherited mutations in the pmp22 gene result in the nonconservative leucine-to-proline (L16P) or glycine-toaspartic acid (G160D) replacements in the PMP22 protein in the Tr J or Tr mouse, respectively (Suter et al., 1992a,b). These mutations are believed to be responsible for the PNS deficits. The majority of human patients with CMT, however, do not have point mutations in the PMP22 gene, but instead harbor a submicroscopic chromosomal duplication on human chromosome 17p11.2-12, which encompasses the PMP22 gene (for review, see Suter and Snipes, 1995a). The similarity of the disease phenotypes, including disease progression, as well as the finding of the identical Tr J single point mutation in a severely affected CMT disease type 1A (CMT1A) family (Valentijn et al., 1992) substantiates the use of these mice as models of human disease and provide a system for elucidating the biology of the PMP22 protein.The ways in which pmp22 mutations perturb myelination are complex, particularly because the function of the PMP22 protein is unknown (for review, see Suter and Snipes, 1995b). Previous morphological studies of the Tr J mouse used the close linkage of the Tr J phenotype to the vestigial tail marker on mouse chromosome 11 to predict the ...

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“…Hypermyelination in CMT1A may be explained by elevated messenger RNA 42 and PMP22 protein expression; Vallat et al 39 were able to show a twofold increase in PMP22 protein expression in sural nerve biopsies of 2 CMT1A patients applying ultrastructural immunocytochemical quantitative analysis. Gabreëls-Festen et al 8 suggest that the myelin sheath gradually becomes too thick for the axon and consequently demyelination occurs.…”

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confidence: 97%