A novel GJB1 frameshift mutation produces a transient CNS symptom of X-linked Charcot–Marie–Tooth disease

Sakaguchi, Hidetsugu; Yamashita, Satoshi; Miura, Akiko; Hirahara, Tomoo; Maeda, Yasushi; Terasaki, Tadashi; Hirano, Teruyuki; Uchino, Makoto

doi:10.1007/s00415-010-5752-8

Cited by 26 publications

(20 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The results of clinical studies are in agreement with pathological studies showing that the severity of changes in CMT1X nerve biopsies are not associated with particular GJB1 mutations (Hahn et al, 2000;Nakagawa et al, 2001;Hattori et al, 2003). Moreover, a GJB1 frameshift mutation caused a CNS phenotype similar to those caused by missense mutations (Sakaguchi et al, 2011), suggesting that CNS phenotypes in CMT1X also lack any consistent genotype-phenotype correlation.…”

Section: Genetic and Neurobiological Basis Of Cmt1xsupporting

confidence: 84%

The Role of Gap Junctions in Charcot-Marie-Tooth Disease

Kleopa¹

2011

J. Neurosci.

View full text Add to dashboard Cite

Section: Genetic and Neurobiological Basis Of Cmt1xsupporting

confidence: 84%

The Role of Gap Junctions in Charcot-Marie-Tooth Disease

Kleopa¹

2011

J. Neurosci.

View full text Add to dashboard Cite

“…Sakaguchi et al 42 reported a 15-year-old male with a novel GJB1 mutation who presented with left hemiparesis. MRI demonstrated hyperintensity in T2 and reduced diffusion in the posterior centrum semiovale and splenium of the corpus callosum, which resolved in days.…”

Section: Resultsmentioning

confidence: 99%

Hereditary and inflammatory neuropathies: a review of reported associations, mimics and misdiagnoses

Rajabally

Adams

Latour

et al. 2016

J Neurol Neurosurg Psychiatry

View full text Add to dashboard Cite

International audienceDistinguishing between hereditary and inflammatory neuropathy is usually straightforward on clinical grounds with the help of a family history. There are nevertheless cases where the distinction is less clear. The advent of molecular genetics has in the past several years aided confirmatory diagnosis for an increasing proportion of patients with genetic neuropathy. Various reports have described associations of Charcot-Marie-Tooth disease with a suspected or confirmed inflammatory neuropathy occasionally responding to immunotherapy. Possible predisposition to an inflammatory component was suggested in a subset of patients. Such reports have, however, been relatively few in number, suggesting the rarity of such associations and of such a predisposition if it exists. There have been a number of publications detailing clinical presentations suggestive of inflammatory neuropathy in patients with a known or later proven genetic aetiology, and subsequently felt to be part of the phenotype rather than representing an association. A number of genetically mediated multisystemic diseases with neuropathy have otherwise been reported as mimicking chronic inflammatory demyelinating polyneuropathy (CIDP). The most common example is that of familial amyloid polyneuropathy, of particular concern for the clinician when misdiagnosed as CIDP, in view of the therapeutic implications. We review the literature on reported associations, mimics and misdiagnoses of hereditary and inflammatory neuropathy and attempt to determine a practical approach to the problem in clinical practice using clinical features, electrophysiology, histopathology and targeted early genetic testing. The issue of attempting immunomodulatory therapy is discussed in view of the published literature

show abstract

“…The ubiquitin-proteasome system has previously been implicated in the ER-associated degradation of wild type and mutant connexins [25, 31–33]. The simplest explanation for the faster degradation of G38D is that most of the protein undergoes proteasomal degradation before it can reach the plasma membrane and form gap junction plaques (probably in early compartments of the secretory pathway).…”

Section: Discussionmentioning

confidence: 99%

Degradation of a connexin40 mutant linked to atrial fibrillation is accelerated

Gemel

Simon

Patel

et al. 2014

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Several Cx40 mutants have been identified in patients with atrial fibrillation (AF). We have been working to identify physiological or cell biological abnormalities of several these human mutants that might explain how they contribute to disease pathogenesis. Wild type (wt) Cx40 or four different mutants (P88S, G38D, V85I, and L229M) were expressed by transfection of communication-deficient HeLa cells or HL-1 cardiomyocytes. Biophysical channel properties and the sub-cellular localization and protein levels of Cx40 were characterized. Wild type Cx40 and all mutants except P88S formed gap junction plaques and induced significant gap junctional conductances. The functional mutants showed only modest alterations of single channel conductances or gating by trans-junctional voltage as compared to wtCx40. However, immunoblotting indicated that the steady state levels of G38D, V85I, and L229M were reduced relative to wtCx40; most strikingly, G38D was only 20 − 31% of wild type levels. After inhibition of protein synthesis with cycloheximide, G38D (and to a lesser extent the other mutants) disappeared much faster than wtCx40. Treatment with the proteasomal inhibitor, epoxomicin, greatly increased levels of G38D and restored the abundance of gap junctions and the extent of intercellular dye transfer. Thus, G38D, V85I, and L229M are functional mutants of Cx40 with small alterations of physiological properties, but accelerated degradation by the proteasome. These findings suggest a novel mechanism (protein instability) for the pathogenesis of AF due to a connexin mutation and a novel approach to therapy (protease inhibition).

show abstract

A novel GJB1 frameshift mutation produces a transient CNS symptom of X-linked Charcot–Marie–Tooth disease

Cited by 26 publications

References 22 publications

The Role of Gap Junctions in Charcot-Marie-Tooth Disease

The Role of Gap Junctions in Charcot-Marie-Tooth Disease

Hereditary and inflammatory neuropathies: a review of reported associations, mimics and misdiagnoses

Degradation of a connexin40 mutant linked to atrial fibrillation is accelerated

Contact Info

Product

Resources

About