| Transport of Trembler-J mutant peripheral myelin protein 22 is blocked in the intermediate compartment and affects the transport of the wild-type protein by direct interaction. | |
| | |
MedLine Citation:
|
PMID: 10066256 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
A R Tobler; L Notterpek; R Naef; V Taylor; U Suter; E M Shooter |
Related Documents
:
|
11898586 - The genetic convergence of charcot-marie-tooth disease types 1 and 2 and the role of ge... 23474776 - A novel homozygous mutation of the nicotinamide nucleotide transhydrogenase gene in a j... 9648876 - Metabolic dysfunction in familial, but not sporadic, amyotrophic lateral sclerosis. 16707726 - Gja12 mutations in children with recessive hypomyelinating leukoencephalopathy. 1691986 - Identification of genetically high risk individuals to lung cancer by dna polymorphisms... 15522806 - Intragenomic variation of the rdna internal transcribed spacers in sponges (phylum pori... |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
|
Title: The Journal of neuroscience : the official journal of the Society for Neuroscience Volume: 19 ISSN: 0270-6474 ISO Abbreviation: J. Neurosci. Publication Date: 1999 Mar |
Date Detail:
|
Created Date: 1999-04-13 Completed Date: 1999-04-13 Revised Date: 2007-11-14 |
Medline Journal Info:
|
Nlm Unique ID: 8102140 Medline TA: J Neurosci Country: UNITED STATES |
Other Details:
|
Languages: eng Pagination: 2027-36 Citation Subset: IM |
Affiliation:
|
Department of Neurobiology, Stanford University School of Medicine, Stanford, California 94305-5125, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Biological Transport / physiology COS Cells Dimerization Epitopes / physiology Mice Mice, Neurologic Mutants / metabolism* Mutation / physiology* Myelin Proteins / chemistry, genetics, immunology, metabolism* Reference Values Schwann Cells / metabolism |
| Grant Support | |
ID/Acronym/Agency:
|
NS04270/NS/NINDS NIH HHS; NS09694/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Epitopes; 0/Myelin Proteins; 0/Pmp22 protein, mouse |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Cloning and characterization of RGS9-2: a striatal-enriched alternatively spliced product of the RGS...
Next Document: GABA- and glutamate-activated channels in green fluorescent protein-tagged gonadotropin-releasing ho...