PMID- 25771809
OWN - NLM
STAT- MEDLINE
DCOM- 20160414
LR  - 20231213
IS  - 1364-6753 (Electronic)
IS  - 1364-6745 (Linking)
VI  - 16
IP  - 3
DP  - 2015 Jul
TI  - A start codon CMT1X mutation associated with transient encephalomyelitis causes 
      complete loss of Cx32.
PG  - 193-200
LID - 10.1007/s10048-015-0442-4 [doi]
AB  - X-linked Charcot-Marie-Tooth disease (CMTX1) results from numerous mutations in 
      the GJB1 gene encoding the gap junction protein connexin32 (Cx32) and is one of 
      the commonest forms of inherited neuropathy. Owing to the expression of Cx32 not 
      only in Schwann cells but also in oligodendrocytes, a subset of CMT1X patients 
      develops central nervous system (CNS) clinical manifestations in addition to 
      peripheral neuropathy. While most GJB1 mutations appear to cause peripheral 
      neuropathy through loss of Cx32 function, the cellular mechanisms underlying the 
      CNS manifestations remain controversial. A novel start codon GJB1 mutation 
      (p.Met1Ile) has been found in a CMT1X patient presenting with recurrent episodes 
      of transient encephalomyelitis without apparent signs of peripheral neuropathy. 
      In order to clarify the functional consequences of this mutation, we examined the 
      cellular expression of two different constructs cloned from genomic DNA including 
      the mutated start codon. None of the cloned constructs resulted in detectable 
      expression of Cx32 by immunocytochemistry or immunoblot, although mRNA was 
      produced at normal levels. Furthermore, co-expression with the other major 
      oligodendrocyte connexin, Cx47, had no negative effect on GJ formation by Cx47. 
      Finally, lysosomal and proteasomal inhibition in cells expressing the start codon 
      mutant constructs failed to recover any detection of Cx32 as a result of impaired 
      protein degradation. Our results indicate that the Cx32 start codon mutation is 
      equivalent to a complete loss of the protein with failure of translation, 
      although transcription is not impaired. Thus, complete loss of Cx32 function is 
      sufficient to produce CNS dysfunction with clinical manifestations.
FAU - Sargiannidou, Irene
AU  - Sargiannidou I
AD  - Neurology Clinics and Neuroscience Laboratory, Cyprus School of Molecular 
      Medicine, The Cyprus Institute of Neurology and Genetics, P. O. Box 23462, 1683, 
      Nicosia, Cyprus.
FAU - Kim, Gun-Ha
AU  - Kim GH
FAU - Kyriakoudi, Styliana
AU  - Kyriakoudi S
FAU - Eun, Baik-Lin
AU  - Eun BL
FAU - Kleopa, Kleopas A
AU  - Kleopa KA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150315
PL  - United States
TA  - Neurogenetics
JT  - Neurogenetics
JID - 9709714
RN  - 0 (Codon, Initiator)
RN  - 0 (Connexins)
RN  - Charcot-Marie-Tooth disease, X-linked, 1
SB  - IM
MH  - Charcot-Marie-Tooth Disease/*complications/*genetics
MH  - Codon, Initiator
MH  - Connexins/*genetics
MH  - Encephalomyelitis/*complications
MH  - HeLa Cells
MH  - Humans
MH  - Gap Junction beta-1 Protein
EDAT- 2015/03/17 06:00
MHDA- 2016/04/15 06:00
CRDT- 2015/03/17 06:00
PHST- 2014/12/05 00:00 [received]
PHST- 2015/03/02 00:00 [accepted]
PHST- 2015/03/17 06:00 [entrez]
PHST- 2015/03/17 06:00 [pubmed]
PHST- 2016/04/15 06:00 [medline]
AID - 10.1007/s10048-015-0442-4 [doi]
PST - ppublish
SO  - Neurogenetics. 2015 Jul;16(3):193-200. doi: 10.1007/s10048-015-0442-4. Epub 2015 
      Mar 15.