Increased gene dosage of myelin protein zero causes Charcot-Marie-Tooth disease
Article first published online: 24 JAN 2012
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 71, Issue 1, pages 84–92, January 2012
How to Cite
Maeda, M. H., Mitsui, J., Soong, B.-W., Takahashi, Y., Ishiura, H., Hayashi, S., Shirota, Y., Ichikawa, Y., Matsumoto, H., Arai, M., Okamoto, T., Miyama, S., Shimizu, J., Inazawa, J., Goto, J. and Tsuji, S. (2012), Increased gene dosage of myelin protein zero causes Charcot-Marie-Tooth disease. Ann Neurol., 71: 84–92. doi: 10.1002/ana.22658
- Issue published online: 24 JAN 2012
- Article first published online: 24 JAN 2012
- Accepted manuscript online: 31 OCT 2011 06:43AM EST
- Manuscript Accepted: 14 OCT 2011
- Manuscript Revised: 29 SEP 2011
- Manuscript Received: 14 JUN 2011
- Grant-in-Aid for Scientific Research on Innovative Areas. Grant Number: 22129002
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Health and Labour Sciences Research Grant on Intractable Diseases from the Ministry of Health, Labour, and Welfare of Japan
On the basis of the hypothesis that copy number mutations of the genes encoding myelin compact proteins are responsible for myelin disorders in humans, we have explored the possibility of copy number mutations in patients with Charcot-Marie-Tooth disease (CMT) whose responsible genes remain undefined.
A family with 6 affected members in 3 consecutive generations, presenting with motor and sensory demyelinating polyneuropathy, was investigated. Characteristic clinical features in this pedigree include Adie pupils and substantial intrafamilial variability in the age at onset, electrophysiological findings, and clinical severity. Nucleotide sequence analyses of PMP22, MPZ, or GJB1 and gene dosage study of PMP22 did not reveal causative mutations. Hence, we applied a custom-designed array for comparative genomic hybridization (CGH) analysis to conduct a comprehensive screening of copy number mutations involving any of the known causative genes for CMT other than PMP22.
The array CGH analyses revealed increased gene dosage involving the whole MPZ, and the flanking genes of SDHC and C1orf192. The gene dosage is estimated to be 5 copies. This mutation showed complete cosegregation with the disease phenotype in this pedigree.
The increased gene dosage of MPZ and increased expression level of MPZ mRNA emphasize the important role of the dosage of the MPZ protein in the functional integrity of peripheral nerve myelin in humans, and provide a new insight into the pathogenic mechanisms underlying CMT. ANN NEUROL 2012;71:84–92