Advances in Charcot–Marie–Tooth Disease Research: Cellular Function of CMT-Related Proteins, Transgenic Animal Models, and Pathomechanisms

Müller, Hans; Suter, Ueli; Broeckhoven, Christine Van

doi:10.1006/nbdi.2000.0309

Cited by 4 publications

(6 citation statements)

References 11 publications

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“…Many examples of mutations leading to protein misfolding and ultimately to disease have been described (for review, see Muller et al, 1997). Among them are the mutations in PLP, a CNS tetraspan myelin protein, that lead to Pelizaeus-Merzbacher disease (Hodes et al, 1993;Griffiths et al, 1995).…”

Section: A Comparison Of Trj-pmp22 and Tr-pmp22 Localizationmentioning

confidence: 99%

“…Studies of animal models expressing altered levels of mutant PM P22 indicate that PM P22 is required for the formation and maintenance of PNS myelin (Adlkofer et al, 1995(Adlkofer et al, , 1997aHuxley et al, 1996;Magyar et al, 1996;Sereda et al, 1996). Point mutations in the gene for PM P22 and, especially, duplication or deletion of the PM P22 gene are responsible for a set of dominantly inherited peripheral neuropathies in humans and mice (for review, see Muller et al, 1997).…”

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confidence: 99%

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Transport ofTrembler-JMutant Peripheral Myelin Protein 22 Is Blocked in the Intermediate Compartment and Affects the Transport of the Wild-Type Protein by Direct Interaction

et al. 1999

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Peripheral myelin protein 22 (PMP22) is an integral membrane protein that is essential for the normal formation and maintenance of peripheral myelin. Duplications, deletions, or mutations in the PMP22 gene account for a set of dominantly inherited peripheral neuropathies. The heterozygous Trembler-J (TrJ) genotype in mice is similar genetically to a Charcot-Marie-Tooth disease type 1A pedigree in humans, whereas the homozygous TrJ condition leads to the most severe form of PMP22-associated neuropathies. To characterize the consequences of the TrJ mutation, we labeled wild-type (wt-) and TrJ-PMP22 in the third loop of the protein with different epitope tags and expressed them separately or together in COS7 cells and primary Schwann cells. Here we show that the transport of the mutant TrJ-PMP22 is interrupted in the intermediate compartment, preventing its insertion into the plasma membrane and affecting the morphology of the endoplasmic reticulum. In addition, TrJ-PMP22 forms a heterodimer with the wt-PMP22. This interaction causes a fraction of the wt-PMP22 to be retained with TrJ-PMP22 in the intermediate compartment of COS7 and Schwann cells. The relative stability of a wt-mutant PMP22 heterodimer as compared with the wt-wt PMP22 homodimer may determine whether a particular mutation is semidominant or dominant. The neuropathy itself appears to result both from decreased trafficking of wt-PMP22 to the plasma membrane and from a toxic gain of function via the accumulation of wt- and TrJ-PMP22 in the intermediate compartment.

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Section: A Comparison Of Trj-pmp22 and Tr-pmp22 Localizationmentioning

confidence: 99%

mentioning

confidence: 99%

Transport ofTrembler-JMutant Peripheral Myelin Protein 22 Is Blocked in the Intermediate Compartment and Affects the Transport of the Wild-Type Protein by Direct Interaction

et al. 1999

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“…33,34 In addition, PMP22 might regulate apoptosis in NIH3T3 fibroblasts but not in cultured Schwann cells. 32,40 Recent results from human nerve biopsies 18 and from mouse models 15 (also our unpublished data) indicate, however, that increased Schwann cell apoptosis is found in vivo associated with altered PMP22 gene dosage. However, the exact contribution of these processes to the pathogenesis of CMT1A remains to be clarified.…”

Section: Discussionmentioning

confidence: 82%

Transgenic Mouse Models of CMT1A and HNPP

Suter¹,

Nave

1999

Annals of the New York Academy of Sciences

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We have generated several PMP22 animal mutants with altered PMP22 gene dosage. A moderate increase in the number of PMP22 genes led to hypomyelination comparable to CMT1A, whereas high copy numbers of transgenic PMP22 resulted in phenotypes resembling more severe forms of hereditary motor and sensory neuropathies. In contrast, eliminating one of the two normal PMP22 genes by gene targeting caused unstable focal hypermyelination (tomacula) similar to the pathology in HNPP. A related but more severe phenotype was observed in mice that lack PMP22 completely. Detailed analysis of the different PMP22 mutants revealed, in addition to the obvious myelinopathy, distal axonopathy as a characteristic feature. We conclude that the maintenance of axons might be a promising target for therapeutic interventions in these demyelinating hereditary neuropathies. Furthermore, our results strongly support the concept that PMP22-related neuropathies (and most likely also other forms of inherited motor and sensory neuropathies) should be viewed as the consequence of impaired neuron-Schwann cell interactions that are likely already to be operative during development. Such considerations should be taken into account in the design of potential novel treatment strategies.

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“…Changes in the amount or in the conformation of one of those components could perturb myelin structure, leading to demyelination as revealed by an increasing number of spontaneous and engineered rodent mutants 31–33 and by genotype‐phenotype correlations in hereditary peripheral neuropathies in humans. 34,35…”

Section: Novel Association Of Pmp22 and P0: Implications For The Strumentioning

confidence: 99%

New Vistas on the Pathomechanism of Charcot‐Marie‐Tooth and Related Peripheral Neuropathies

1999

Annals of the New York Academy of Sciences

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A gene-dosage mechanism in CMT1A and HNPP has been postulated previously. Here, recent findings are discussed concerning (i) the functional consequences of altered PMP22 expression on Schwann cell growth regulation and on the capacity of genetically modified Schwann cells to myelinate peripheral axons, (ii) the cell physiological effects caused by the expression of certain disease-related missense mutations of PMP22 that are known to alter the Schwann cell phenotype and impair myelination in vivo, and (iii) the pathomechanism of CMT1 in light of findings on a novel association between PMP22 and P0 in PNS myelin.

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Advances in Charcot–Marie–Tooth Disease Research: Cellular Function of CMT-Related Proteins, Transgenic Animal Models, and Pathomechanisms

Cited by 4 publications

References 11 publications

Transport ofTrembler-JMutant Peripheral Myelin Protein 22 Is Blocked in the Intermediate Compartment and Affects the Transport of the Wild-Type Protein by Direct Interaction

Transport ofTrembler-JMutant Peripheral Myelin Protein 22 Is Blocked in the Intermediate Compartment and Affects the Transport of the Wild-Type Protein by Direct Interaction

Transgenic Mouse Models of CMT1A and HNPP

New Vistas on the Pathomechanism of Charcot‐Marie‐Tooth and Related Peripheral Neuropathies

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