Human Molecular Genetics Advance Access published online on March 12, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn083
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Different Cellular and Molecular Mechanisms for Early and Late-onset Myelin Protein Zero Mutations
Department of Neurosciences, Ophthalmology and Genetics
University of Genova
16132 Genova, Italy
Institute of Molecular Bioimaging and Physiology (IBFM)-Section of Genova
Italian National Research Council
16132 Genova, Italy
Department of Experimental Medicine, Biochemistry Section
University of Genova
16132 Genova, Italy
Department of Neurology and Center for Molecular Medicine and Genetics
Wayne State University
48201 Detroit, MI, USA
Institute of Molecular Bioimaging and Physiology (IBFM)-Section of Genova
Italian National Research Council
16132 Genova, Italy
Department of Neurosciences, Ophthalmolgy and Genetics
University of Genova
16132 Genova, Italy
Department of Neurology and Center for Molecular Medicine and Genetics
Wayne State University
48201 Detroit, MI, USA
Department of Neurosciences, Ophthalmology and Genetics
University of Genova
16132 Genova, Italy
Department of Neurosciences, Ophthalmology and Genetics
University of Genova
16132 Genova, Italy
Department of Experimental Medicine
University of Genova
16132 Genova, Italy
Department of Neurosciences, Ophthalmolgy and Genetics
University of Genova
16132 Genova, Italy
Department of Neurology and Center for Molecular Medicine and Genetics
Wayne State University
48201 Detroit, MI, USA
Department of Neurology and Center for Molecular Medicine and Genetics
Wayne State University
48201 Detroit, MI, USA
Department of Neurosciences, Ophthalmolgy and Genetics
University of Genova
16132 Genova, Italy
Institute of Molecular Bioimaging and Physiology (IBFM)-Section of Genova
Italian National Research Council
16132 Genova
Italy
Corresponding Author Marina Grandis Department of Neurosciences, Ophthalmolgy and Genetics University of Genova 16132 Genova, Italy Tel: 0039-010-3537057 Fax: 0039-010-3538639 e-mail: mgrandis{at}neurologia.unige.it
Received February 19, 2008; Revised February 19, 2008; Accepted March 10, 2008
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 wild type MPZ 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.
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