Sensorineural deafness in X-linked Charcot-Marie-Tooth disease with connexin 32 mutation (R142Q)

Stojkovic, Tanya; Latour, Philippe; Vandenberghe, Antoon; Hurtevent, J. F.; Vermersch, Patrick

doi:10.1212/wnl.52.5.1010

Cited by 83 publications

(40 citation statements)

References 34 publications

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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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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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“…Hearing impairment and other central nervous system (CNS) symptoms have been reported in CMTX patients with several types of Cx32 mutations (Nicholson and Corbett 1996;Nicholson et al 1998;Bähr et al 1999;Stojkovic et al 1999). One of the common sural nerve findings in CMTX is a loss of myelinated fibers, especially large fibers, and thin myelination.…”

Section: X-linkedmentioning

confidence: 99%

Phenotypes of X-linked Charcot-Marie-Tooth disease and altered trafficking of mutant Connexin 32 (GJB1)

et al. 2001

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To clarify the pathomechanism in three patients with X-linked Charcot-Marie-Tooth disease (CMTX) and unique clinical features, we studied three connexin (Cx) 32 (GJB1) mutants with respect to cellular localization in cultured cells. Wild-type Cx32 and three Cx32 mutants (Val63Ile and Glu186Lys, obtained from CMTX patients with hearing impairment; and Arg22Gln, obtained from a CMTX patient with a fair number of onion-bulb formations) were transfected to rat pheochromocytoma cells (PC12). We investigated the expression of Cx32 protein in each clone by immunoblotting and immunohistochemical staining. While Cx32 protein with the Arg22Gln mutation was detectable immunohistochemically only in the cytoplasm, Cx32 protein with the Val63Ile or Glu186Lys mutation was detected in both the plasma membrane and the cytoplasm. Cx32 protein with the wild-type sequence was detected mostly in the plasma membrane, with plaques indicating the existence of active gap junction formation. These three Cx32 mutations associated with CMTX patients with unique clinical and pathological findings caused altered trafficking of the Cx32 protein. These altered expressions indicated loss of active gap junction formation with different expression abnormalities in these CMTX patients.

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“…Deafness in patients with CMT disease is a rare entity and it has been reported to be accompanied with CMT1, CMT2, Xlinked dominant CMT (CMTX), hereditary motor and sensory neuropathy-Lom (HMSNL), and Dejerine-Sottas disease (DSD) [5][6][7][8][9]. Several genes, such as PMP22, myelin protein zero (MPZ), Connexin 32 (Cx-32) and N-myc downstreamregulated gene 1 (NDRG1) are known to be responsible for these disorders.…”

Section: Introductionmentioning

confidence: 99%

A novel point mutation in PMP22 gene associated with a familial case of Charcot-Marie-Tooth disease type 1A with sensorineural deafness

Joo

et al. 2004

Neuromuscular Disorders

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Sensorineural deafness in X-linked Charcot-Marie-Tooth disease with connexin 32 mutation (R142Q)

Abstract: CMTX due to Cx32 mutations often shows interfamilial and intrafamilial phenotypic variation, which is also the hallmark of this family. The sensorineural deafness observed in this family suggests that Cx32 could play an important role in the auditory pathway.

Cited by 83 publications

References 34 publications

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

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

Phenotypes of X-linked Charcot-Marie-Tooth disease and altered trafficking of mutant Connexin 32 (GJB1)

A novel point mutation in PMP22 gene associated with a familial case of Charcot-Marie-Tooth disease type 1A with sensorineural deafness

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