PMP22 expression in dermal nerve myelin from patients with CMT1A
Open Access
- 15 May 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Brain
- Vol. 132 (7), 1734-1740
- https://doi.org/10.1093/brain/awp113
Abstract
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.This publication has 52 references indexed in Scilit:
- Diabetes mellitus exacerbates motor and sensory impairment in CMT1AJournal of the Peripheral Nervous System, 2008
- Charcot-Marie-Tooth Neuropathies: Diagnosis and ManagementSeminars in Neurology, 2008
- Different cellular and molecular mechanisms for early and late-onset myelin protein zero mutationsHuman Molecular Genetics, 2008
- Ablation of the UPR-Mediator CHOP Restores Motor Function and Reduces Demyelination in Charcot-Marie-Tooth 1B MiceNeuron, 2008
- Antiprogesterone therapy uncouples axonal loss from demyelination in a transgenic rat model of CMT1A neuropathyAnnals of Neurology, 2007
- Loss‐of‐function phenotype of hereditary neuropathy with liability to pressure palsiesMuscle & Nerve, 2003
- The phenotypic manifestations of chromosome 17p11.2 duplicationBrain, 1997
- Peripheral myelin protein‐22 expression in charcot‐marie‐tooth disease type 1a sural nerve biopsiesJournal of Neuroscience Research, 1994
- Charcot — Marie — Tooth neuropathy type 1A with both duplication and non-duplicationHuman Molecular Genetics, 1993
- Molecular Genetics and Neuropathology of Charcot‐Marie‐Tooth Disease Type 1ABrain Pathology, 1992