Journal article
Different cellular and molecular mechanisms for early and late-onset myelin protein zero mutations
Human molecular genetics, Vol.17(13), pp.1877-1889
07/01/2008
DOI: 10.1093/hmg/ddn083
PMID: 18337304
Abstract
Mutations in the gene MPZ, encoding myelin protein zero (MPZ), cause inherited neuropathies collectively called Charcot-Marie-Tooth type 1B (CMT1B). Based on the age of onset, clinical and pathological features, most MPZ mutations are separable into two groups: one causing a severe, early-onset, demyelinating neuropathy and a second, causing a late-onset neuropathy with prominent axonal loss. To investigate potential pathomechanisms underlying the two phenotypes, we transiently transfected HeLa cells with two late-onset (T95M, H10P) and two early-onset (H52R, S22_W28 deletion) mutations and analyzed their effects on intracellular protein trafficking, glycosylation, cell viability and intercellular adhesion. We found that the two late-onset mutations were both transported to the cell membrane and moderately reduced MPZ-mediated intercellular adhesion. The two early-onset mutations caused two distinct abnormalities. H52R was correctly glycosylated and trafficked to the plasma membrane, but strongly affected intercellular adhesion. When co-expressed with wild-type MPZ (wtMPZ), a functional dominant negative effect was observed. Alternatively, S22_W28 deletion was retained within the cytoplasm and reduced both adhesion caused by wtMPZ and cellular viability. Since the same trafficking patterns were observed in transfected murine Schwann cells, they are not an artifact of heterologous cell expression. Our results suggest that at least some late-onset mutations cause a partial loss of function in the transfected cells, whereas multiple abnormal gain of function pathways can result in early-onset neuropathy. Further characterization of these pathways will lead to a better understanding of the pathogenesis of CMT1B and a rational basis for treating these debilitating inherited neuropathies.
Details
- Title: Subtitle
- Different cellular and molecular mechanisms for early and late-onset myelin protein zero mutations
- Creators
- Marina Grandis - Department of Neurosciences, Ophthalmology and Genetics, Universityof Genova, 16132 Genova, Italy. mgrandis@neurologia.unige.itTiziana VigoMario PassalacquaManisha JainSara ScazzolaVeronica La PadulaMichelle BrucalFederica BenvenutoLucilla NobbioAngela CadoniGian Luigi MancardiJohn KamholzMichael E ShyAngelo Schenone
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.17(13), pp.1877-1889
- Publisher
- England
- DOI
- 10.1093/hmg/ddn083
- PMID
- 18337304
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Grant note
- R01 NS041319 / NINDS NIH HHS GGP06178 / Telethon
- Language
- English
- Date published
- 07/01/2008
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984020797202771
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