CMT 1B and MPZ Mutations (Different Cellular and Molecular Mechanisms for Early

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Hum Mol Genet. 2008 Mar 12

Different Cellular and Molecular Mechanisms for Early and Late-onset

Myelin Protein Zero Mutations.

Grandis M, Vigo T, Passalacqua M, Jain M, Scazzola S, La Padula V,

Brucal M, Benvenuto F, Nobbio L, Cadoni A, Mancardi GL, Kamholz J,

Shy ME, Schenone A.

Department of Neurosciences, Ophthalmology and Genetics University of

Genova 16132 Genova, Italy.

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.