Probing Myelin Protein Zero Gain of Function Mutants

Lawrence Wrabetz, Maurizio D’Antonio, Maria Pennuto, Gabriele Dati, Elisa Tinelli, Pietro Fratta, Stefano Previtali, Daniele Imperiale, Jurgen Zielasek, Klaus Toyka, Robin L. Avila, Daniel A. Kirschner, Albee Messing, M. Laura Feltri, and Angelo Quattrini
The P0 glycoprotein is the most abundant protein in myelinated nerves. The extracellular immunoglobulin-like fold forms tetramers in trans that allow for the compaction of myelin layers. Although mutations in myelin protein zero [MPZ], P0) are well-known causes of neuropathy, the clinical phenotypes vary widely, in contrast to the mild abnormalities caused by heterozygous loss of function. Thus Wrabetz et al. explored the hypothesis that MPZ-neuropathies are attributable to gain of function mutations. They examined transgenic mice expressing MPZ mutations at S63, either S63del or S63C. S63del is the mutation underlying an adult-onset demyelinating neuropathy (Charcot-Marie-Tooth, Type 1B [CMT1B]), whereas the S63C mutation causes an early-onset demyelinating neuropathy Déjérine-Sottas syndrome). Both mutant alleles caused a demyelinating neuropathy despite the coexistence of normal alleles, consistent with a gain of function mechanism. S63C caused a packing defect in the myelin, whereas S63C was retained in the endoplasmic reticulum and elicited a presumably toxic unfolded protein response. [From Medical News Today.]

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