Dejerine-Sottas neuropathy in mother and son with same point mutation of PMP22 gene

Ionâşescu, Victor; Searby, Charles; Ionasescu, Rebecca; Chatkupt, S.; Patel, N.; Koenigsberger, Richard

doi:10.1002/(sici)1097-4598(199701)20:1<97::aid-mus13>3.0.co;2-z

Cited by 74 publications

(39 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…NCVs are comparably affected in Trembler-J mice (9 m/s) as in humans with the identical mutation (9 -15 m/s) (Valentijn et al, 1992;Hoogendijk et al, 1993). NCV are even slower (5 m/s) in Trembler mice (Low and McLeod, 1977) and humans with the identical missense mutation (Gly150Asp) (Suter et al, 1992b;Ionasescu et al, 1997), which correlate with their more severe demyelinating neuropathy (Low, 1976a,b;Henry et al, 1983;Beuche and Friede, 1985;Friede, 1986). Humans with the other missense mutations also present severe phenotypes and severely slowed NCVs (Fabrizi et al, , 2000Simonati et al, Fabrizi et al, 2001) (for review, see Nelis et al, 1999).…”

Section: Electrophysiological Alterations In Chronic Demyelinationmentioning

confidence: 99%

Altered Ion Channels in an Animal Model of Charcot-Marie-Tooth Disease Type IA

Devaux¹,

Scherer²

2005

J. Neurosci.

View full text Add to dashboard Cite

How demyelination and remyelination affect the function of myelinated axons is a fundamental aspect of demyelinating diseases. We examined this issue in Trembler-J mice, a genetically authentic model of a dominantly inherited demyelinating neuropathy of humans. The K ϩ channels Kv1.1 and Kv1.2 channels were often improperly located in the paranodal axon membrane, typically associated with improperly formed paranodes, and in unmyelinated segments between internodes. As in wild-type nerves, Trembler-J nodes contained Nav1.6, ankyrin-G, ␤IV-spectrin, and KCNQ2, but, unlike wild-type nerves, they also contained Kv3.1b and Nav1.8. In unmyelinated segments bordered by myelin sheaths, these proteins were clustered in heminodes and did not appear to be diffusely localized in the unmyelinated segments themselves. Nodes and heminodes were contacted by Schwann cells processes that did not have the ultrastructural or molecular characteristics of mature microvilli. Despite the presence of Nav1.8, a tetrodotoxin-resistant sodium channel, sciatic nerve conduction was at least as sensitive to tetrodotoxin in Trembler-J nerves as in wild-type nerves. Thus, the profound reorganization of axonal ion channels and the aberrant expression of novel ion channels likely contribute to the altered conduction in Trembler-J nerves.

show abstract

Section: Electrophysiological Alterations In Chronic Demyelinationmentioning

confidence: 99%

Altered Ion Channels in an Animal Model of Charcot-Marie-Tooth Disease Type IA

Devaux¹,

Scherer²

2005

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…In addition, point mutations have been found in patients with Charcot-Marie-Tooth disease, hereditary neuropathy with liability to pressure palsies, and DejerineSottas syndrome (4). Indeed, the first missense mutations to be identified in the PMP-22 gene were found in the Tr (5) and Tr-J (6) mice with identical point mutations shared between humans and mice (7,8).…”

mentioning

confidence: 99%

Association of calnexin with mutant peripheral myelin protein-22 ex vivo : A basis for “gain-of-function” ER diseases

Dickson

Bergeron

Shames

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

108

110

View full text Add to dashboard Cite

The function of PMP-22 is unknown, but roles in cell growth, apoptosis, higher order macromolecular structure, and intracellular signaling have been proposed (1). Intrachromosomal duplications (2) and deletions (3) encompassing PMP-22 cause Charcot-MarieTooth disease and hereditary neuropathy with liability to pressure palsies, respectively. In addition, point mutations have been found in patients with Charcot-Marie-Tooth disease, hereditary neuropathy with liability to pressure palsies, and DejerineSottas syndrome (4). Indeed, the first missense mutations to be identified in the PMP-22 gene were found in the Tr (5) and Tr-J (6) mice with identical point mutations shared between humans and mice (7, 8).Many PMP-22 mutations are retained intracellularly (9-12) and appear to belong to a growing class of mutations termed ''endoplasmic reticulum (ER) retention mutations'' that are recognized by ER resident-folding proteins, molecular chaperones, and͞or other enzymes that serve to monitor the fidelity of protein synthesis and macromolecular assembly (13,14). Among ER retention diseases, however, heritable neuropathies caused by PMP-22 mutation or overexpression are unique because they are dominant gain-of-function diseases (15).Here, transient and glucosylation-dependent association of PMP-22 with the ER chaperone calnexin (CNX) was observed. PMP-22 associated only with CNX. Formation of intracellular myelin-like figures (IMLFs) in transfected cells coincided with the cosequestration of CNX in a glucosylation dependent fashion. Similar intracellular myelin-like structures were present in the sciatic nerves of homozygous Tr-J mice. These results provide a mechanistic explanation for the human Charcot-Marie-Tooth disease secondary to the ER retention of mutant PMP-22 via the CNX cycle and provide an unexpected link between the gain-offunction phenotype of such diseases and sequestration of the resident ER lectin chaperone, CNX. Materials and MethodsMetabolic Labeling, Immunoprecipitations, and Western Blot Analysis.Metabolic labeling and pulse-chase of mouse sciatic nerves and immunoprecipitations for PMP-22 (16) as well as nondenaturing CNX immunoprecipitations, BiP immunoprecipitation, and ATP depletion of cell lysates have been described (17, 18). For sequential PMP-22 immunoprecipitations, lysates were first CNX immunoprecipitated as described (17) followed by resolubilization in 0.5% SDS in 50 mM Tris (pH 8.0) and PMP-22 immunoprecipitated in modified radioimmunoprecipitation assay buffer (50 mM Tris, pH 8.0͞150 mM NaCl͞1% deoxycholate containing 0.5% Nonidet P-40). Samples were electrophoresed, transferred to nitrocellulose membranes, and exposed to film by using the Kodak Biomax Transcreen LE system (NEN). For some experiments, sciatic nerves were pretreated with 1 mM castanospermine (SigmaAldrich) for 1 h at 37°C before and during metabolic labeling. Samples were then homogenized in 2% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate lysis buffer containing 5 mM iodoacetamide and gels processed for fluo...

show abstract

“…PNS myelin alterations are more severe in homozygous TrJ and Tr animals compared with heterozygous, suggesting a gene dosage effect. Furthermore, the identical TrJ single mutation has been found in a family affected by a severe form of CMT1A disease (Valentijn et al, 1992), whereas the Tr amino acid substitution was detected in two patients suffering from DejerineSottas demyelinating neuropathy (Ionasescu et al, 1997). Thus, Tr and TrJ mice are regarded as animal models for CMT1A neuropathy.…”

mentioning

confidence: 99%

Overloaded Endoplasmic Reticulum–Golgi Compartments, a Possible Pathomechanism of Peripheral Neuropathies Caused by Mutations of the Peripheral Myelin Protein PMP22

et al. 1998

View full text Add to dashboard Cite

Nonconservative point mutations of the peripheral myelin protein 22 (PMP22) are associated with Charcot-Marie-Tooth type 1A disease, the most common inherited peripheral neuropathy in humans, and with the Trembler J (TrJ) and Trembler (Tr) alleles in mice. We investigated the intracellular transport of wild-type PMP22 and its TrJ and Tr mutant forms in Schwann cells and in a non-neuronal cell line. In contrast to wild type, mutant proteins were not inserted into the plasma membrane and accumulated in the endoplasmic reticulum and Golgi compartments. Coexpression of each mutant with wild-type PMP22 confirmed the different intracellular distribution of the mutant forms, indicating that neither the TrJ nor Tr protein has a dominantnegative effect on the cellular distribution of wild-type PMP22. Accumulation of PMP22 immunoreactivity in the cell body of myelinating Schwann cells was also observed in nerve biopsies obtained from CMT1A patients carrying the TrJ point mutation. We propose that impaired trafficking of mutated PMP22 affects Schwann cell physiology leading to myelin instability and loss.

show abstract

Dejerine-Sottas neuropathy in mother and son with same point mutation of PMP22 gene

Cited by 74 publications

References 8 publications

Altered Ion Channels in an Animal Model of Charcot-Marie-Tooth Disease Type IA

Altered Ion Channels in an Animal Model of Charcot-Marie-Tooth Disease Type IA

Association of calnexin with mutant peripheral myelin protein-22 ex vivo : A basis for “gain-of-function” ER diseases

Overloaded Endoplasmic Reticulum–Golgi Compartments, a Possible Pathomechanism of Peripheral Neuropathies Caused by Mutations of the Peripheral Myelin Protein PMP22

Contact Info

Product

Resources

About