An animal model for Charcot-Marie-Tooth disease type 4B1
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID 2311604
Author(s) Bonneick, Sonja; Boentert, Matthias; Berger, Philipp; Atanasoski, Suzana; Mantei, Ned; Wessig, Carsten; Toyka, Klaus V.; Young, Peter; Suter, Ueli
Author(s) at UniBasel Atanasoski, Suzana
Year 2005
Title An animal model for Charcot-Marie-Tooth disease type 4B1
Journal Human Molecular Genetics
Volume 14
Number 23
Pages / Article-Number 3685-3695
Abstract Charcot-Marie-Tooth disease (CMT) comprises a family of clinically and genetically very heterogeneous hereditary peripheral neuropathies and is one of the most common inherited neurological disorders. We have generated a mouse model for CMT type 4B1 using embryonic stem cell technology. To this end, we introduced a stop codon into the Mtmr2 locus within exon 9, at the position encoding amino acid 276 of the MTMR2 protein (E276X). Concomitantly, we have deleted the chromosomal region immediately downstream of the stop codon up to within exon 13. The resulting allele closely mimics the mutation found in a Saudi Arabian CMT4B1 patient. Animals homozygous for the mutation showed various degrees of complex myelin infoldings and outfoldings exclusively in peripheral nerves, in agreement with CMT4B1 genetics and pathology. Mainly, paranodal regions of the myelin sheath were affected, with a high degree of quantitative and qualitative variability between individuals. This pathology was progressive with age, and axonal damage was occasionally observed. Distal nerve regions were more affected than proximal parts, in line with the distribution in CMT. However, we found no significant electrophysiological changes, even in aged (16-month-old) mice, suggesting that myelin infoldings and outfoldings per se are not invariably associated with detectable electrophysiological abnormalities. Our animal model provides a basis for future detailed molecular and cellular studies on the underlying disease mechanisms in CMT4B1. Such an analysis will reveal how the disease develops, in particular, the enigmatic myelin infoldings and outfoldings as well as axonal damage, and provide mechanistic insights that may aid in the development of potential therapeutic approaches.
Publisher Oxford University Press
ISSN/ISBN 0964-6906 ; 1460-2083
Full Text on edoc No
Digital Object Identifier DOI 10.1093/hmg/ddi400
PubMed ID
ISI-Number WOS:000233668600013
Document type (ISI) Article

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