Abstract:
:Charcot-Marie-Tooth disease type-1A (CMT1A) is one of the most common types of inherited peripheral nerve diseases. It is caused by the trisomy of chromosome 17p12 (c17p12), a large DNA segment of 1.4 Mb containing PMP22 plus eight other genes. The size of c17p12 is formidable for any cloning technique to manipulate, and thus precludes production of models in vitro and in vivo that can precisely recapitulate the genetic alterations in humans with CMT1A. This limitation and other factors have led to several assumptions, which have yet been carefully scrutinized, serving as key principles in our understanding of the disease. For instance, one extra copy of c17p12 in patients with CMT1A results in a higher gene dosage of PMP22, thereby expected to produce a higher level of PMP22 mRNA/proteins that cause the disease. However, there has been increasing evidence that PMP22 levels are highly variable among patients with CMT1A and may fall into the normal range at a given time point. This raises an alternative mechanism causing the disease by dysregulation of PMP22 expression or excessive fluctuation of PMP22 levels, not the absolute increase of PMP22. This has become a pressing issue since recent clinical trials using ascorbic acid failed to alter the clinical outcome of CMT1A patients, leaving no effective therapy for the disease. In this article, we will discuss how this fundamental issue might be investigated. In addition, several other key issues in CMT1A will be discussed, including potential mechanisms responsible for the uniform slowing of conduction velocities. A clear understanding of these issues could radically change how therapies should be developed against CMT1A.
journal_name
Ann Clin Transl Neuroljournal_title
Annals of clinical and translational neurologyauthors
Li Jdoi
10.1002/acn3.432subject
Has Abstractpub_date
2017-06-15 00:00:00pages
601-607issue
8issn
2328-9503pii
ACN3432journal_volume
4pub_type
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journal_title:Annals of clinical and translational neurology
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doi:10.1002/acn3.136
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.35
更新日期:2014-02-01 00:00:00
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更新日期:2014-08-01 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.736
更新日期:2019-03-27 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.74
更新日期:2014-07-01 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章,评审
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更新日期:2017-08-10 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
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更新日期:2018-01-09 00:00:00
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更新日期:2018-09-20 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.553
更新日期:2018-04-16 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.121
更新日期:2014-10-01 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.50835
更新日期:2019-08-01 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
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更新日期:2019-01-22 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
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更新日期:2017-05-17 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.173
更新日期:2015-04-01 00:00:00
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journal_title:Annals of clinical and translational neurology
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doi:10.1002/acn3.320
更新日期:2016-06-02 00:00:00
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更新日期:2020-01-01 00:00:00
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更新日期:2020-06-01 00:00:00
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journal_title:Annals of clinical and translational neurology
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更新日期:2020-09-01 00:00:00
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journal_title:Annals of clinical and translational neurology
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更新日期:2020-01-01 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.51179
更新日期:2020-12-18 00:00:00