Six novel connexin32 (GJB1) mutations in X-linked Charcot-Marie-Tooth disease

Lee, Ming-Jen; Nelson, Isabelle; Houlden, Henry; Mg, Sweeney; Hilton‐Jones, David; Blake, Julian; Wood, Nicholas W.; Reilly, Mary M.

doi:10.1136/jnnp.73.3.304

Cited by 60 publications

(52 citation statements)

References 18 publications

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“…He exhibited the typical MRI findings: bilateral symmetric hyperintensity lesions on T2-weighted images and fluid attenuated inversion recovery (FLAIR) images and decreased apparent diffusion coefficient of the centrum semiovale and splenium [8,9]. According to previous reports, the CNS dysfunction was mostly caused by missense mutations in the GJB1 gene; alternatively, a sole study [10] reported a nonsense mutation (E109x) that caused a cerebellar lesion on MRI without CNS symptoms, and a frameshift mutation (T191fs) that associated with Babinski sign in the patient. Therefore, this is the first report that a frameshift mutation produces a transient CNS phenotype of CMT1X.…”

Section: Discussionmentioning

confidence: 93%

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

et al. 2010

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X-linked Charcot-Marie-Tooth disease (CMT1X) is the second most common variant of CMT and is caused by mutations in the GJB1 gene encoding connexin 32. Some CMT1X patients with GJB1 missense mutations have shown transient central nervous system (CNS) symptoms with abnormal brain magnetic resonance imaging (MRI). Herein we report the first case with a novel GJB1 frameshift mutation that associates with a transient CNS symptom. The patient noticed high-arched feet and limited ankle dorsiflexion in early childhood; he transiently developed numbness and paresis of left face and arm, and dysphagia, with abnormal brain MRI. Although the CNS symptoms recovered within several hours without treatment, intravenous immunoglobulin (IVIg) therapy ameliorated progressing symptoms such as those of toe extensor muscles. His mother had been diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP), and repetitive IVIg treatments had relieved the symptoms. Therefore, inflammation might be involved in the pathophysiology of CMT1X with the GJB1 mutation, while molecular analysis revealed that the mutant GJB1 was more rapidly degraded by the proteasome pathway known as endoplasmic reticulum (ER)-associated degradation.

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Section: Discussionmentioning

confidence: 93%

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

et al. 2010

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“…In CMT disease due to connexin 32 (Cx32, GJB1) mutations multifocal and in some cases transient and recurrent white matter lesions have been demonstrated by MRI of the brain [17,21,23]. In two male patients with X-linked CMT due to Cx32 mutations transient ataxia, dysarthria and weakness were associated with transient symmetrical white matter abnormalities on MRI.…”

Section: Discussionmentioning

confidence: 99%

Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations

et al. 2008

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■ Abstract Mutations in the mitofusin 2 (MFN2) gene are a major cause of primary axonal CharcotMarie-Tooth (CMT) neuropathy. This study aims at further characterization of cerebral white matter alterations observed in patients with MFN2 mutations. Molecular genetic, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) investigations were performed in four unrelated patients aged 7 to 38 years with early onset axonal CMT neuropathy. Three distinct and so far undescribed MFN2 mutations were detected. Two patients had secondary macrocephaly and mild diffuse predominantly periventricular white matter alterations on MRI. In addition, one boy had symmetrical T2-hyperintensities in both thalami. Two patients had optic atrophy, one of them with normal MRI. In three patients proton MRS revealed elevated concentrations of total N-acetyl compounds (neuronal marker), total creatine (found in all cells) and myo-inositol (astrocytic marker) in cerebral white and gray matter though with regional variation. These alterations were most pronounced in the two patients with abnormal MRI. DTI of these patients revealed mild reductions of fractional anisotropy and mild increase of mean diffusivity in white matter. The present findings indicate an enhanced cellular density in cerebral white matter of MFN2 neuropathy which is primarily due to a reactive gliosis without axonal damage and possibly accompanied by mild demyelination.

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“…In mammalian glia, the connexin genes CX32/GJB1 and CX47 are known targets of Sox10 function Schlierf et al, 2006). Connexins play crucial roles in the inner ear: mutations in CX26/GJB2 and CX30/GJB6 account for the most common form of inherited deafness (DFNB1) in humans, whereas mutations in CX32/GJB1 have been implicated in causing the sensorineural deafness in Charcot-Marie-Tooth disease (Stojkovic et al, 1999;Lee et al, 2002). Our data indicate that expression of the orthologous connexin genes cx27.5 and cx33.8 is lost in zebrafish sox10 mutant ears at 72-74 hpf.…”

Section: Research Articlementioning

confidence: 99%

A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle

Dutton

Abbas

Spencer

et al. 2009

Disease Models &Amp; Mechanisms

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SUMMARYIn humans, mutations in the SOX10 gene are a cause of the auditory-pigmentary disorder Waardenburg syndrome type IV (WS4) and related variants. SOX10 encodes an Sry-related HMG box protein essential for the development of the neural crest; deafness in WS4 and other Waardenburg syndromes is usually attributed to loss of neural-crest-derived melanocytes in the stria vascularis of the cochlea. However, SOX10 is strongly expressed in the developing otic vesicle and so direct roles for SOX10 in the otic epithelium might also be important. Here, we examine the otic phenotype of zebrafish sox10 mutants, a model for WS4. As a cochlea is not present in the fish ear, the severe otic phenotype in these mutants cannot be attributed to effects on this tissue. In zebrafish sox10 mutants, we see abnormalities in all otic placodal derivatives. Gene expression studies indicate deregulated expression of several otic genes, including fgf8, in sox10 mutants. Using a combination of mutant and morphant data, we show that the three sox genes belonging to group E (sox9a, sox9b and sox10) provide a link between otic induction pathways and subsequent otic patterning: they act redundantly to maintain sox10 expression throughout otic tissue and to restrict fgf8 expression to anterior macula regions. Single-cell labelling experiments indicate a small and transient neural crest contribution to the zebrafish ear during normal development, but this is unlikely to account for the strong defects seen in the sox10 mutant. We discuss the implication that the deafness in WS4 patients with SOX10 mutations might reflect a haploinsufficiency for SOX10 in the otic epithelium, resulting in patterning and functional abnormalities in the inner ear.

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Six novel connexin32 (GJB1) mutations in X-linked Charcot-Marie-Tooth disease

Cited by 60 publications

References 18 publications

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

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

Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations

A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle

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