Molecular alterations resulting from frameshift mutations in peripheral myelin p

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J Neurosci Res. 2005 Nov 4

Molecular alterations resulting from frameshift mutations in

peripheral myelin protein 22: Implications for neuropathy severity.

JS, Roux KJ, Fletcher BS, Fortun J, Notterpek L.

Department of Neuroscience, College of Medicine, McKnight Brain

Institute, University of Florida, Gainesville, Florida.

Alterations in peripheral myelin protein 22 (PMP22) expression are

associated with a heterogeneous group of hereditary demyelinating

peripheral neuropathies. Two mutations at glycine 94, a single

guanine insertion or deletion in PMP22, result in different reading

frameshifts and, consequently, an extended G94fsX222 or a truncated

G94fsX110 protein, respectively. Both of these autosomal dominant

mutations alter the second half of PMP22 and yet are linked to

clinical phenotypes with distinct severities. The G94fsX222 is

associated with hereditary neuropathy with liability to pressure

palsies, whereas G94fsX110 causes severe neuropathy diagnosed as

Dejerine-Sottas disease or Charcot-Marie-Tooth disease type IA. To

investigate the subcellular changes associated with the G94

frameshift mutations, we expressed epitope-tagged forms in primary

rat Schwann cells. Biochemical and immunolabeling studies indicate

that, unlike the wild-type protein, which is targeted for the plasma

membrane, frameshift PMP22s are retained in the cell, prior to

reaching the medial Golgi compartment. Similar to Wt-PMP22, both

frameshift mutants are targeted for proteasomal degradation and

accumulate in detergent-insoluble, ubiquitin-containing aggregates

upon inhibition of this pathway. The extended frameshift PMP22 shows

the ability to form spontaneous aggregates in the absence of

proteasome inhibition. On the other hand, Schwann cells expressing

the truncated protein proliferate at a significantly higher rate than

Schwann cells expressing the wild-type or the extended PMP22. In

summary, these results suggest that a greater potential for PMP22

aggregation is associated with a less severe phenotype, whereas

dysregulation of Schwann cell proliferation is linked to severe

neuropathy. (