Pathogenetic role of the deafness-related M34T mutation of Cx26

Bicego, Massimiliano; Beltramello, Martina; Melchionda, Salvatore; Carella, Massimo; Piazza, Valeria; Zelante, Leopoldo; Bukauskas, Feliksas F.; Arslan, Edoardo; Cama, Elona; Pantano, Sergio; Bruzzone, Roberto; D’Andrea, Paola; Mammano, Fabio

doi:10.1093/hmg/ddl184

Cited by 70 publications

(78 citation statements)

References 71 publications

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“…Since the M34T substitution of hCx26 was reported to be the cause of nonsyndromic hearing loss (11), the functional role of the position 34 has been studied, and it has been suggested that M34T leads to a constriction of the channel pore (12). In our work, it is conceivable that the plug in the pore is locked into place by the hCx26M34A mutation because the physical obstruction is consistent with the decreased permeability of the hCx26M34A mutation (13).…”

Section: Discussionsupporting

confidence: 52%

“…The hCx26M34A mutant is a single-site mutation at the same position as the hCx26M34T mutant, which can cause prelingual nonsyndromic hereditary deafness (11). Although not as well characterized as hCx26M34T (12), this single-point mutation of a Met to Ala decreases dye coupling in exogenously transfected HeLa cells and forms structures indistinguishable from wild-type gap junctions (13). We succeeded in making 2D crystals of the hCx26M34A suitable for cryoelectron crystallography.…”

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confidence: 99%

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Three-dimensional structure of a human connexin26 gap junction channel reveals a plug in the vestibule

Oshima

Tani²,

Hiroaki³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

178

179

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Connexin molecules form intercellular membrane channels facilitating electronic coupling and the passage of small molecules between adjoining cells. Connexin26 (Cx26) is the second smallest member of the gap junction protein family, and mutations in Cx26 cause certain hereditary human diseases such as skin disorders and hearing loss. Here, we report the electron crystallographic structure of a human Cx26 mutant (M34A). Although crystallization trials used hemichannel preparations, the density map revealed that two hemichannels redocked at their extracellular surfaces into full intercellular channels. These orthorhombic crystals contained two sets of symmetry-related intercellular channels within three lipid bilayers. The 3D map shows a prominent density in the pore of each hemichannel. This density contacts the innermost helices of the surrounding connexin subunits at the bottom of the vestibule. The density map suggests that physical blocking may play an important role that underlies gap junction channel regulation. Our structure allows us to suggest that the two docked hemichannels can be independent and may regulate their activity autonomously with a plug in the vestibule.connexin channels ͉ electron crystallography ͉ intercellular communication ͉ membrane protein structure ͉ two-dimensional crystals

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Section: Discussionsupporting

confidence: 52%

mentioning

confidence: 99%

Three-dimensional structure of a human connexin26 gap junction channel reveals a plug in the vestibule

Oshima

Tani²,

Hiroaki³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

178

179

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“…For example, the residual permeability of the Cx26 mutant F83L for monovalent ions such as K + is reported to be 72% of the wild-type (Bruzzone et al 2003) and that of M34T 11% of the wild-type (Bicego et al 2006). Furthermore, mutations such as 35delG, V37I, W77R, L90P, S113R, M163V, 167delT, and R184P result in a complete loss of function with residual conductivity≤1% of the wild-type values (Bicego et al 2006;Bruzzone et al 2003). Other mutations, such as V84L, although reducing the conductivity for metabolites (Beltramello et al 2005), were not considered here.…”

Section: Cx26 Mutations Reducing Intercellular Connectivity (35delg)mentioning

confidence: 99%

“…These are well documented as leading to deafness in human populations. Missense mutations such as M34T or R75W have a dominant negative effect on hearing (Rabionet et al 2000) and functional analysis of such mutations have identified reduced ionic conductivity of the gap junction (GJ) as the associated defect (Bicego et al 2006;Bruzzone et al 2003). It has also been proposed that mutations such as V84L, with reduced permeability to metabolites such as IP 3 (Beltramello et al 2005) may exert their effect by interfering with the development and maintenance of the organ of Corti.…”

Section: Introductionmentioning

confidence: 99%

Reduced Electromotility of Outer Hair Cells Associated with Connexin-Related Forms of Deafness: An In silico Study of a Cochlear Network Mechanism

Mistrík¹,

Ashmore²

2010

JARO

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Mutations in the GJB2 gene encoding for the connexin 26 (Cx26) protein are the most common source of nonsyndromic forms of deafness. Cx26 is a building block of gap junctions (GJs) which establish electrical connectivity in distinct cochlear compartments by allowing intercellular ionic (and metabolic) exchange. Animal models of the Cx26 deficiency in the organ of Corti seem to suggest that the hearing loss and the degeneration of outer hair cells (OHCs) and inner hair cells is due to failed K + and metabolite homeostasis. However, OHCs can develop normally in some mutants, suggesting that the hair cells death is not the universal mechanism. In search for alternatives, we have developed an in silico large scale three-dimensional model of electrical current flow in the cochlea in the small signal, linearised, regime. The effect of mutations was analysed by varying the magnitude of resistive components representing the GJ network in the organ of Corti. The simulations indeed show that reduced GJ conductivity increases the attenuation of the OHC transmembrane potential at frequencies above 5 kHz from 6.1 dB/decade in the wild-type to 14.2 dB/decade. As a consequence of increased GJ electrical filtering, the OHC transmembrane potential is reduced by up to 35 dB at frequencies 910 kHz. OHC electromotility, driven by this potential, is crucial for sound amplification, cochlear sensitivity and frequency selectivity. Therefore, we conclude that reduced OHC electromotility may represent an additional mechanism underlying deafness in the presence of Cx26 mutations and may explain lowered OHC functionality in particular reported Cx26 mutants.

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“…Another GJB2 mutation, M34T, found in a child with bilateral moderate to severe hearing loss, was thought to be a polymorphism (9). However, a recent study suggested that it could be pathologic even in the heterozygous state (18). The G160S mutation has been described by others as a polymorphism (19,20).…”

Section: Resultsmentioning

confidence: 99%

GJB2 and GJB6 Mutations in Children with Congenital Cytomegalovirus Infection

et al. 2007

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Congenital cytomegalovirus (CMV) infection is a leading cause of sensorineural hearing loss (SNHL) in children. Whether connexin mutations are factors in the development of CMV-related hearing loss has not been explored. We examined gap junction protein beta-2 (GJB2) and gap junction protein beta-6 (GJB6) mutations in 149 children with congenital CMV infection and 380 uninfected neonates. Mutations in GJB2 and GJB6 were assessed by nucleotide sequencing and polymerase chain reaction (PCR) methods, respectively. The study population was predominantly African American, and 4.3% of the subjects were carriers of a connexin 26 mutation. The overall frequency of GJB2 mutations was significantly higher in the group of children with CMV infection and hearing loss (21%) compared with those with CMV infection and normal hearing (3%, p ϭ 0.017) and the group of uninfected newborns (3.9%, p ϭ 0.016). Eight previously reported mutations (M34T, V27I, R127H, F83L, R143W, V37I, V84L, G160S), and four novel mutations (V167M, G4D, A40T, and R160Q) were detected. None of the study children had the 342-kb deletion (delGJB6-D13S1830) in GJB6, which suggests that this mutation does not play a role in hereditary deafness in the African American population. Although GJB2 mutations were detected in children with and without CMV-related hearing loss, those with hearing loss had a higher frequency of GJB2 mutations.

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Pathogenetic role of the deafness-related M34T mutation of Cx26

Cited by 70 publications

References 71 publications

Three-dimensional structure of a human connexin26 gap junction channel reveals a plug in the vestibule

Three-dimensional structure of a human connexin26 gap junction channel reveals a plug in the vestibule

Reduced Electromotility of Outer Hair Cells Associated with Connexin-Related Forms of Deafness: An In silico Study of a Cochlear Network Mechanism

GJB2 and GJB6 Mutations in Children with Congenital Cytomegalovirus Infection

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