CMT1X phenotypes represent loss of GJB1 gene function

M E Shy; C Siskind; E R Swan; K M Krajewski; T Doherty; D R Fuerst; P J Ainsworth; R A Lewis; S S Scherer; A F Hahn

doi:10.1212/01.wnl.0000256709.08271.4d

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CMT1X phenotypes represent loss of GJB1 gene function

Journal article

Peer reviewed

CMT1X phenotypes represent loss of GJB1 gene function

M E Shy, C Siskind, E R Swan, K M Krajewski, T Doherty, D R Fuerst, P J Ainsworth, R A Lewis, S S Scherer and A F Hahn

Neurology, Vol.68(11), pp.849-855

03/13/2007

DOI: 10.1212/01.wnl.0000256709.08271.4d

PMID: 17353473

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Abstract

To investigate possible genotype-phenotype correlations and to evaluate the natural history of patients with Charcot-Marie-Tooth disease type 1X (CMT1X). CMT1X is caused by over 260 distinct mutations in the gap junction beta 1 (GJB1) gene, located on the X chromosome, which encodes the gap junction protein connexin 32 (Cx32). The natural history of CMT1X is poorly understood, and it remains unknown whether particular mutations cause more severe neuropathies through abnormal gain-of-function mechanisms. We evaluated 73 male patients with CMT1X, who each have 1 of 28 different GJB1 mutations predicted to affect nearly all domains of Cx32. Disability was evaluated quantitatively by the CMT Neuropathy Score (CMTNS) as well as by the CMT Symptom Score (CMTSS) and the CMT Examination Score (CMTES), which are both based on the CMTNS. Patients were also evaluated by neurophysiology. In all patients, disability increased with age, and the degree of disability was comparable with that observed in patients with a documented GJB1 deletion. Disability correlated with a loss of motor units as assessed by motor unit number estimates. Taken together, these data suggest that most GJB1 mutations cause neuropathy by a loss of normal connexin 32 function. Therefore, treatment of male patients with Charcot-Marie-Tooth disease type 1X may prove amenable to gene replacement strategies.

Mutation

Phenotype

Age Factors

Humans

Middle Aged

Gene Silencing

Connexins - genetics

Male

Charcot-Marie-Tooth Disease - pathology

Charcot-Marie-Tooth Disease - genetics

Adolescent

Adult

Aged

Charcot-Marie-Tooth Disease - epidemiology

Retrospective Studies

Child

Details

Title: Subtitle: CMT1X phenotypes represent loss of GJB1 gene function
Creators: M E Shy - Department of Neurology, Wayne State University, 421 E. Canfield, Detroit, MI 48201, USA. m.shy@wayne.edu
C Siskind
E R Swan
K M Krajewski
T Doherty
D R Fuerst
P J Ainsworth
R A Lewis
S S Scherer
A F Hahn
Resource Type: Journal article
Publication Details: Neurology, Vol.68(11), pp.849-855
Publisher: United States
DOI: 10.1212/01.wnl.0000256709.08271.4d
PMID: 17353473
ISSN: 0028-3878
eISSN: 1526-632X
Grant note: R01NS43168-01A1 / NINDS NIH HHS
Language: English
Date published: 03/13/2007
Academic Unit: Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
Record Identifier: 9984020771002771

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