Distinct disease mechanisms in peripheral neuropathies due to altered peripheral

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Neurobiol Dis. 2005 Apr;18(3):656-68.

(NOTE: Mentions CMT)

Distinct disease mechanisms in peripheral neuropathies due to altered

peripheral myelin protein 22 gene dosage or a Pmp22 point mutation.

Giambonini-Brugnoli G, Buchstaller J, Sommer L, Suter U, Mantei N.

Institute for Cell Biology, Department of Biology, ETH-Honggerberg,

Swiss Federal Institute of Technology, Schafmattstrasse 18, CH-8093

Zurich, Switzerland.

Point mutations affecting PMP22 can cause hereditary demyelinating

and dysmyelinating peripheral neuropathies. In addition, duplication

and deletion of PMP22 are associated with Charcot-Marie-Tooth disease

Type 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure

Palsy (HNPP), respectively.

This study was designed to elucidate disease processes caused by

misexpression of Pmp22 and, at the same time, to gain further

information on the controversial molecular function of PMP22. To this

end, we took advantage of the unique resource of a set of various

Pmp22 mutant mice to carry out comparative expression profiling of

mutant and wild-type sciatic nerves. Tissues derived from Pmp22-/-

( " knockout " ), Pmp22tg (increased Pmp22 copy number), and Trembler

(Tr; point mutation in Pmp22) mutant mice were analyzed at two

developmental stages: (i) at postnatal day (P)4, when normal

myelination has just started and primary causative defects of the

mutations are expected to be apparent, and (ii) at P60, with the goal

of obtaining information on secondary disease effects.

Interestingly, the three Pmp22 mutants exhibited distinct profiles of

gene expression, suggesting different disease mechanisms. Increased

expression of genes involved in cell cycle regulation and DNA

replication is characteristic and specific for the early stage in

Pmp22-/- mice, supporting a primary function of PMP22 in the

regulation of Schwann cell proliferation. In the Tr mutant, a

distinguishing feature is the high expression of stress response

genes. Both Tr and Pmp22tg mice show strongly reduced expression of

genes important for cholesterol synthesis at P4, a characteristic

that is common to all three mutants at P60.

Finally, we have identified a number of candidate genes that may play

important roles in the disease process or in myelination per se.