CMT 1A: PMP22 expression in dermal nerve myelin from patients

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Brain. 2009 May 15.

PMP22 expression in dermal nerve myelin from patients with CMT1A.

Katona I, Wu X, Feely SM, Sottile S, Siskind CE, LJ, Shy ME, Li J.

1 Department of Neurology, Wayne State University, Detroit, MI, USA.

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a 1.4 Mb duplication on

chromosome 17p11.2, which contains the peripheral myelin protein-22 (PMP22)

gene. Increased levels of PMP22 in compact myelin of peripheral nerves have been

demonstrated and presumed to cause the phenotype of CMT1A.

The objective of the present study was to determine whether an extra copy of the

PMP22 gene in CMT1A disrupts the normally coordinated expression of PMP22

protein in peripheral nerve myelin and to evaluate PMP22 over-expression in

patients with CMT1A and determine whether levels of PMP22 are molecular markers

of disease severity.

PMP22 expression was measured by taking skin biopsies from patients with CMT1A

(n = 20) and both healthy controls (n = 7) and patients with Hereditary

Neuropathy with liability to Pressure Palsies (HNPP) (n = 6), in which patients

have only a single copy of PMP22.

Immunological electron microscopy was performed on the skin biopsies to quantify

PMP22 expression in compact myelin. Similar biopsies were analysed by real time

PCR to measure PMP22 mRNA levels. Results were also correlated with impairment

in CMT1A, as measured by the validated CMT Neuropathy Score.

Most, but not all patients with CMT1A, had elevated PMP22 levels in myelin

compared with the controls. The levels of PMP22 in CMT1A were highly variable,

but not in HNPP or the controls.

However, there was no correlation between neurological disabilities and the

level of over-expression of PMP22 protein or mRNA in patients with CMT1A. The

extra copy of PMP22 in CMT1A results in disruption of the tightly regulated

expression of PMP22.

Thus, variability of PMP22 levels, rather than absolute level of PMP22, may play

an important role in the pathogenesis of CMT1A.