Journal Article

Different cellular and molecular mechanisms for early and late-onset myelin protein zero mutations

Marina Grandis, Tiziana Vigo, Mario Passalacqua, Manisha Jain, Sara Scazzola, Veronica La Padula, Michelle Brucal, Federica Benvenuto, Lucilla Nobbio, Angela Cadoni, Gian Luigi Mancardi, John Kamholz, Michael E. Shy and Angelo Schenone

in Human Molecular Genetics

Volume 17, issue 13, pages 1877-1889
Published in print July 2008 | ISSN: 0964-6906
Published online March 2008 | e-ISSN: 1460-2083 | DOI:
Different cellular and molecular mechanisms for early and late-onset myelin protein zero mutations

Show Summary Details


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.

Journal Article.  8219 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.