Increased gene dosage of myelin protein zero causes Charcot-Marie-Tooth disease

• Published in: Annals of neurology Vol. 71; no. 1; pp. 84 - 92
• Main Authors: Maeda, Meiko Hashimoto, Mitsui, Jun, Soong, Bing-Wen, Takahashi, Yuji, Ishiura, Hiroyuki, Hayashi, Shin, Shirota, Yuichiro, Ichikawa, Yaeko, Matsumoto, Hideyuki, Arai, Makoto, Okamoto, Tomoko, Miyama, Sahoko, Shimizu, Jun, Inazawa, Johji, Goto, Jun, Tsuji, Shoji
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.01.2012; Wiley-Liss; Wiley Subscription Services, Inc
• Subjects: Adult; Biological and medical sciences; Charcot-Marie-Tooth Disease - diagnosis; Charcot-Marie-Tooth Disease - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Gene Dosage - genetics; Genes; Genetic Linkage - genetics; Humans; Male; Medical sciences; Middle Aged; Mutation; Myelin P0 Protein - genetics; Myelin P0 Protein - physiology; Neurology; Pedigree; Neuromuscular diseases; Nervous system diseases; Myelin; Charcot-Marie-Tooth disease; Central nervous system disease; Degenerative disease; Spinal cord disease; Protein; Genetic disease
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.22658

Objective: 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. Methods: 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. Results: 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. Interpretation: 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