Experimental CMT 1A: A cDNA microarrays analysis

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Mol Cell Neurosci. 2005 Apr;28(4):703-14.

Experimental Charcot-Marie-Tooth type 1A: A cDNA microarrays analysis.

Vigo T, Nobbio L, Hummelen PV, Abbruzzese M, Mancardi G, Verpoorten

N, Verhoeven K, Sereda MW, Nave KA, Timmerman V, Schenone A.

Department of Neurosciences, Ophthalmology and Genetics, University

of Genova, Italy, via De Toni 5, 16132 Genova, Italy; Center of

Excellence for Biomedical Research, University of Genova, Italy,

viale Benedetto XV, 16132 Genova, Italy.

To reveal the spectrum of genes that are modulated in Charcot-Marie-

Tooth neuropathy type 1A (CMT1A), which is due to overexpression of

the gene coding for the peripheral myelin protein 22 (pmp22), we

performed a cDNA microarray experiment with cDNA from sciatic nerves

of a rat model of the disease. In homozygous pmp22 overexpressing

animals, we found a significant down-regulation of 86 genes, while

only 23 known genes were up-regulated, suggesting that the increased

dosage of pmp22 induces a general down-regulation of gene expression

in peripheral nerve tissue.

Classification of the modulated genes into functional categories

leads to the identification of some pathways altered by

overexpression of pmp22. In particular, a selective down-regulation

of the ciliary neurotrophic factor transcript and of genes coding for

proteins involved in cell cycle regulation, for cytoskeletal

components and for proteins of the extracellular matrix, was

observed. Cntf expression was further studied by real-time PCR and

ELISA technique in pmp22 transgenic sciatic nerves, human CMT1A sural

nerve biopsies, and primary cultures of transgenic Schwann cells.

According to the results of cDNA microarray analysis, a down-

regulation of cntf, both at the mRNA and protein level, was found in

all the conditions tested. These results are relevant to reveal the

molecular function of PMP22 and the pathogenic mechanism of CMT1A. In

particular, finding a specific reduction of cntf expression in CMT1A

Schwann cells suggests that overexpression of pmp22 significantly

affects the ability of Schwann cells to offer a trophic support to

the axon, which could be a factor, among other, responsible for the

development of axonal atrophy in human and experimental CMT1A.