Functional Domain Mapping and Selective Trans-dominant Effects Exhibited by Cx26 Disease-causing Mutations

Mutations in Cx26 are a major cause of autosomal dominant and recessive forms of sensorineural deafness. Some mutations in Cx26 are associated not only with deafness but also with skin disease. We examined the subcellular localization and function of two green fluorescent protein (GFP)-tagged Cx26 point mutants that exhibit both phenotypes, G59A-GFP and D66H-GFP. D66H-GFP was retained within the brefeldin A-insensitive trans-Golgi network, whereas a population of G59A-GFP was transported to the cell surface. Neither G59A nor D66H formed gap junctions that were permeable to small fluorescent dyes, suggesting they are loss-of-function mutations. When co-expressed with wild-type Cx26, both G59A and D66H exerted dominant-negative effects on Cx26 function. G59A also exerted a trans-dominant negative effect on co-expressed wild type Cx32 and Cx43, whereas D66H exerted a trans-dominant negative effect on Cx43 but not Cx32. We propose that the severity of the skin disease is dependent on the specific nature of the Cx26 mutation and the trans-dominant selectivity of the Cx26 mutants on co-expressed connexins. Additional systematic mutations at residue D66, in which the overall charge of this motif was altered, suggested that the first extracellular loop is critical for Cx26 transport to the cell surface as well as function of the resulting gap junction channels. Mutations in Cx26 are a major cause of autosomal dominant and recessive forms of sensorineural deafness. Some mutations in Cx26 are associated not only with deafness but also with skin disease. We examined the subcellular localization and function of two green fluorescent protein (GFP)-tagged Cx26 point mutants that exhibit both phenotypes, G59A-GFP and D66H-GFP. D66H-GFP was retained within the brefeldin A-insensitive trans-Golgi network, whereas a population of G59A-GFP was transported to the cell surface. Neither G59A nor D66H formed gap junctions that were permeable to small fluorescent dyes, suggesting they are loss-of-function mutations. When co-expressed with wild-type Cx26, both G59A and D66H exerted dominant-negative effects on Cx26 function. G59A also exerted a trans-dominant negative effect on co-expressed wild type Cx32 and Cx43, whereas D66H exerted a trans-dominant negative effect on Cx43 but not Cx32. We propose that the severity of the skin disease is dependent on the specific nature of the Cx26 mutation and the trans-dominant selectivity of the Cx26 mutants on co-expressed connexins. Additional systematic mutations at residue D66, in which the overall charge of this motif was altered, suggested that the first extracellular loop is critical for Cx26 transport to the cell surface as well as function of the resulting gap junction channels. Gap junctions mediate one method of intercellular communication by allowing for the passage of ions, second messengers, metabolites, and other small molecules. By enabling direct communication between cells, gap junctions are thought to be important for cell proliferation, differentiation, and maintenance of tissue homeostasis (1Loewenstein W.R. Physiol. Rev. 1981; 61: 829-913Google Scholar). Gap junction plaques are composed of a few to hundreds of gap junction channels clustered together. Each individual channel is made up of two hemichannels; one hemichannel (or connexon) is contributed from each of two adjoining cells (2Goodenough D.A. Goliger J.A. Paul D.L. Annu. Rev. Biochem. 1996; 65: 475-502Google Scholar). In turn, each connexon consists of six oligomerized polypeptides called connexins (Cx) 1The abbreviations used are: Cx, connexins; GFP, green fluorescent protein; GJIC, gap junctional intercellular communication; PBS, phosphate-buffered saline; BODIPY, 4,4-difluoro-5,7-dimethyl-4-bora-3a,4adiaza-s-indacene-3-pentanoic acid; TR, Texas Red; BFA, brefeldin A; TGN, trans-Golgi network. (2Goodenough D.A. Goliger J.A. Paul D.L. Annu. Rev. Biochem. 1996; 65: 475-502Google Scholar, 3Bruzzone R. White T.W. Goodenough D.A. Bioessays. 1996; 18: 709-718Google Scholar). It is well established that the Cx family of genes encode the polypeptide subunits that make up gap junctions, and a recent genomic study highlighted the common features of the 19 mouse and 20 human Cx genes (4Willecke K. Eiberger J. Degen J. Eckardt D. Romualdi A. Guldenagel M. Deutsch U. Sohl G. Biol. Chem. 2002; 383: 725-737Google Scholar). Most tissues express more than one member of the Cx family (3Bruzzone R. White T.W. Goodenough D.A. Bioessays. 1996; 18: 709-718Google Scholar, 5De Maio A. Vega V.L. Contreras J.E. J. Cell. Physiol. 2002; 191: 269-282Google Scholar). This is particularly important as connexons composed of different members of the Cx family exhibit selective permeability to fluorescent dyes and endogenous metabolites (6Goldberg G.S. Lampe P.D. Nicholson B.J. Nat. Cell Biol. 1999; 1: 457-459Google Scholar, 7Niessen H. Harz H. Bedner P. Kramer K. Willecke K. J. Cell Sci. 2000; 113: 1365-1372Crossref Google Scholar, 8Bevans C.G. Kordel M. Rhee S.K. Harris A.L. J. Biol. Chem. 1998; 273: 2808-2816Google Scholar, 9Elfgang C. Eckert R. Lichtenberg-Frate H. Butterweck A. Traub O. Klein R.A. Hulser D.F. Willecke K. J. Cell Biol. 1995; 129: 805-817Google Scholar, 10Nicholson B.J. Weber P.A. Cao F. Chang H. Lampe P. Goldberg G. Braz. J. Med. Biol. Res. 2000; 33: 369-378Google Scholar). Altering the subset of Cxs spatially and temporally expressed may allow cells within a tissue to respond differentially to cell signals, leading to specific changes in differentiation. In addition to homomeric connexons, a connexon may be composed of more than one Cx (heteromeric). For example, heteromeric connexons composed of Cx40/Cx43 or Cx26/Cx32 have been characterized and exhibit altered functional properties compared with their homomeric counterparts (8Bevans C.G. Kordel M. Rhee S.K. Harris A.L. J. Biol. Chem. 1998; 273: 2808-2816Google Scholar, 11Brink P.R. Cronin K. Banach K. Peterson E. Westphale E.M. Seul K.H. Ramanan S.V. Beyer E.C. Am. J. Physiol. 1997; 273: C1386-C1396Google Scholar, 12He D.S. Jiang J.X. Taffet S.M. Burt J.M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6495-6500Google Scholar, 13Cottrell G.T. Wu Y. Burt J.M. Cell Commun. Adhes. 2001; 8: 193-197Google Scholar, 14Lee M.J. Rhee S.K. Mol. Cells. 1998; 8: 295-300Google Scholar). These combinations further expand the potential multitude of signals that may pass between cells and highlight the requirement to characterize the intermixing that may occur between different Cxs co-expressed within a cell population. Gap junctions are important for keratinocyte growth and differentiation (15Choudhry R. Pitts J.D. Hodgins M.B. Dev. Dyn. 1997; 210: 417-430Google Scholar). According to a recent study using reverse transcriptase polymerase chain reaction, at least 10 different Cxs are expressed by keratinocytes, including Cx43, Cx32, Cx30, and Cx26 (16Di W.L. Rugg E.L. Leigh I.M. Kelsell D.P. J. Investig. Dermatol. 2001; 117: 958-964Google Scholar, 17Di W.L. Common J.E. Kelsell D.P. Cell Commun. Adhes. 2001; 8: 415-418Google Scholar). It is noteworthy that mutations in Cx26 are responsible for sensorineural deafness and hyperproliferative skin disease in humans (18Maestrini E. Korge B.P. Ocana-Sierra J. Calzolari E. Cambiaghi S. Scudder P.M. Hovnanian A. Monaco A.P. Munro C.S. Hum. Mol. Genet. 1999; 8: 1237-1243Google Scholar, 19Richard G. Smith L.E. Bailey R.A. Itin P. Hohl D. Epstein Jr., E.H. DiGiovanna J.J. Compton J.G. Bale S.J. Nat. Genet. 1998; 20: 366-369Google Scholar, 20Richard G. White T.W. Smith L.E. Bailey R.A. Compton J.G. Paul D.L. Bale S.J. Hum. Genet. 1998; 103: 393-399Google Scholar, 21Kelsell D.P. Wilgoss A.L. Richard G. Stevens H.P. Munro C.S. Leigh I.M. Eur. J. Hum. Genet. 2000; 8: 468Google Scholar). At least four different mutations have been associated with both hearing loss and skin disease including R75W (20Richard G. White T.W. Smith L.E. Bailey R.A. Compton J.G. Paul D.L. Bale S.J. Hum. Genet. 1998; 103: 393-399Google Scholar), D66H (18Maestrini E. Korge B.P. Ocana-Sierra J. Calzolari E. Cambiaghi S. Scudder P.M. Hovnanian A. Monaco A.P. Munro C.S. Hum. Mol. Genet. 1999; 8: 1237-1243Google Scholar, 21Kelsell D.P. Wilgoss A.L. Richard G. Stevens H.P. Munro C.S. Leigh I.M. Eur. J. Hum. Genet. 2000; 8: 468Google Scholar), G59A (22Heathcote K. Syrris P. Carter N.D. Patton M.A. J. Med. Genet. 2000; 37: 50-51Google Scholar), and ΔE42 (23Rouan F. White T.W. Brown N. Taylor A.M. Lucke T.W. Paul D.L. Munro C.S. Uitto J. Hodgins M.B. Richard G. J. Cell Sci. 2001; 114: 2105-2113Google Scholar). Specific symptoms associated with these mutations vary in severity suggesting that mutations within Cx to and subcellular D.P. J. Hodgins M.B. Cell Biol. 2001; Scholar). using that the ΔE42 mutation was to a dominant-negative effect on wild-type Cx26 function a trans-dominant effect on Cx43 channel function (23Rouan F. White T.W. Brown N. Taylor A.M. Lucke T.W. Paul D.L. Munro C.S. Uitto J. Hodgins M.B. Richard G. J. Cell Sci. 2001; 114: 2105-2113Google Scholar). Cx43 and Cx26 are not thought to functional heteromeric or channels C. Eckert R. Lichtenberg-Frate H. Butterweck A. Traub O. Klein R.A. Hulser D.F. Willecke K. J. Cell Biol. 1995; 129: 805-817Google Scholar, T.W. R. S. Paul D.L. Goodenough D.A. J. Cell Biol. Scholar, J.A. Paul D.L. Dev. Dyn. Scholar, E.C. J. A. A.P. P.R. Cell Commun. Adhes. 2001; 8: Scholar), the by which this effect is not (23Rouan F. White T.W. Brown N. Taylor A.M. Lucke T.W. Paul D.L. Munro C.S. Uitto J. Hodgins M.B. Richard G. J. Cell Sci. 2001; 114: 2105-2113Google further that Cx26 skin disease by effects on other Cxs co-expressed in the of Cx in on channel and R. White T.W. Paul D.L. J. Cell Sci. Scholar), this is more for Cx transport and to study two Cx26 D66H-GFP and in well cell When expressed in gap junctional intercellular communication cell the D66H-GFP was retained within the trans-Golgi and a population of the G59A-GFP was transported to the cell surface and of gap mutants were with to permeability compared with wild-type When co-expressed with Cx26, the D66H-GFP was transported to the cell surface but the resulting gap junctions were to suggesting that this exerted a dominant-negative effect on wild-type Cx26 function. D66H-GFP was to a trans-dominant negative effect on Cx43 but not Cx32. G59A-GFP exerted a dominant-negative effect on Cx26 but also a effect on Cx32 and Cx43 function. systematic with and that this is critical not only for Cx26 transport to the cell surface but also for the of functional channels. that the severity of skin is to selective trans-dominant with other Cxs expressed within the Cell tissue were from cells and cells Cx32 by M. of and cells, were in and cell were by with or a or G59A-GFP was expressed in cells or in with Cx32. cells, which express Cx43 were with the Cx26 mutants to cell Cx43 and the Cx26 mutants for the cells and cell P. G. M.A. Res. 1999; were in cells or G59A-GFP or in with Cx26 were by In cells were also to Cx43 and D66H-GFP by of and D66H-GFP was in cells by and and Cx43, Cx30, and Cx26 were by C. C. G. of Cx43 and Cx26 were the A. F. G. J. Res. 1999; as J. D. J. J. Biol. Chem. 2000; Scholar, H. H. J. M.A. J. Biol. Chem. 2002; Scholar). Cx26 mutants and were using the the were used to the Cx26 mutations. in each is to mutation and to other mutations were was used to and to the and of Cx26, or and the resulting were the and for the Cx26 and of the resulting and and G59A-GFP were the and of the A. F. G. J. Res. 1999; Scholar). the Cx26, Cx43, and D66H-GFP were as J. D. J. J. Biol. Chem. 2000; Scholar, H. H. J. M.A. J. Biol. Chem. 2002; Scholar). of and changes and cell at least of cells were to express the of Cxs J. D. J. J. Biol. Chem. 2000; Scholar). These cells were used for and as on the subcellular localization and function of and were using cells with these mutations as within the was with and and the of This of the from the of and D66H-GFP and of and was by using to the For of and cells were to on and with of and of D66H-GFP. of or was cells were and as of cells or D66H-GFP were to a of Goodenough D.A. J. Cell Biol. Scholar). were on two in cells were in in for were in PBS, in in for and with specific for and as of and or cells were in the of or 10 for or cells on were in a of and for 10 by with and for as M. J. Cell Biol. 1995; Scholar). Cx was using a mouse by Y. Y. H. Scholar), mouse and was from and used at a to Texas or were from were and were on a were using 10 of the using the subcellular localization of D66H-GFP more cells D66H-GFP were with brefeldin for up to on were at and the was with that was the in cells on were with for with PBS, and in on Cell a cell (or in the of and wild-type or Cx of two cell to and of were with using and a the were with a and the of cells was At least 20 cells were for each Cx are expressed as the of cells were by of using the of the of and cells and D66H-GFP were in 20 were in H. M.A. J. Biol. Chem. at and the addition of and of to was by the in in 20 for was as H. M.A. J. Biol. Chem. with of were using as and with the of the wild-type and Cx26 were and was using of connexins were using the as a of Cx26 G59A and wild-type Cx26 and G59A and D66H mutants formed gap junctions at the cell these Cxs were expressed in cells H. H. J. M.A. J. Biol. Chem. 2002; Scholar). was transported to the cell surface and formed gap junction plaques in cells G59A-GFP was the cell within a of and at the cell in gap plaques D66H-GFP was retained within a the localization of retained wild-type or Cx26, cells were for a of the small population of both and G59A-GFP localization in the of D66H-GFP on the other with Goodenough D.A. J. Cell Biol. that channel at the cell gap junctions were to by in We cells or D66H-GFP with and that a of or G59A-GFP were at the cell surface. D66H-GFP was that both and associated were to not more the that the D66H-GFP the network, and of the were with M. J. Cell Biol. 1995; Scholar), and cells were examined to the D66H-GFP in the trans-Golgi When cells were with for a population of D66H-GFP not the whereas was to within the cells were with which of the a population of not and the with the population of D66H-GFP these that D66H-GFP is retained within the and that a mutation at residue effects on the of Cx26 to to be transported to the cell surface. Gap by G59A-GFP to the mutations in Cx26 to loss-of-function gap junction cells or D66H-GFP were with and the of cells was to of cells only cells D66H-GFP not gap junction cells D66H-GFP to only cells These were in cells with the G59A and D66H mutants were also to be to the fluorescent that they were loss-of-function mutations not of D66H-GFP to the Cell and Gap specific Cxs the transport of D66H-GFP to the cell examined cells that co-expressed Cx32 or in addition to D66H-GFP and cells that co-expressed Cx26 or Cx43 in addition to D66H-GFP. between wild-type Cx26 and the human D66H-GFP Cx26 in cells with from that with Cx26 in not with the human or the Cx26 When co-expressed with wild-type Cx26, a population of D66H-GFP was transported to the cell surface and gap junction plaques in of wild-type Cx26 within the When D66H-GFP was co-expressed with Cx32, Cx32 was also to the of a population of D66H-GFP gap junction plaques the of and D66H-GFP in D66H-GFP transport and gap junction plaques co-expressed with Cx43, D66H-GFP was retained within the and Cx43 at the cell surface not to be These that D66H-GFP is of transported to the cell surface and gap junctions co-expressed with specific members of the Cx family of wild-type Cx26, Cx32, or Cx43 was expressed in or cells, gap junction plaques were of and to D66H-GFP to the Cell D66H-GFP was retained within the and with specific Cxs was to D66H-GFP transport to the cell the to D66H-GFP at the cell surface was a of of the Cx26 to or for In the of the was in and D66H-GFP compared with cells or D66H-GFP not the of or D66H-GFP and was of D66H-GFP to the cell surface in the of or these that the in D66H-GFP is not the of D66H-GFP a of the Cx26 mutants altered cells with to protein and examined the of Cx26 and Cx26 mutants by and G59A-GFP whereas the D66H-GFP a of these were to the Cx26 and G59A-GFP nor D66H-GFP formed functional gap junctions as by their permeability properties to fluorescent We these mutants were of channels wild-type Cx26 in a dominant-negative cells both wild-type Cx26 and D66H-GFP a in compared with the cells that expressed wild-type Cx26 or Cx26 in with of Cx26 and G59A-GFP to a in that both D66H-GFP and G59A-GFP exhibit a dominant-negative effect on wild-type Cx26 function. D66H-GFP or G59A-GFP a trans-dominant effect on other members of the Cx family that are co-expressed in the examined the effect of these mutants on the function of both Cx32 and the D66H-GFP not have a effect on Cx32 whereas G59A-GFP a in compared with wild-type Cx32 or cells that expressed both Cx32 and in was in cells Cx43 and whereas D66H-GFP exerted a in Cx43 channel permeability These that both D66H-GFP and G59A-GFP dominant-negative effect on wild-type Cx26 and trans-dominant effects on wild-type Cx43 and Cx32. and the at for Cx26 to the Cell and D66H mutation is a of a for a the charge at this is important for in transport of Cx26, other mutations were and and were transported to the cell surface and formed gap junction plaques expressed in cells and was retained within the cell to the D66H-GFP This that the charge at residue is important for transport to the cell surface. We or was mutants formed gap junction plaques that were permeable to a in the chain at residue in transport of Cx26 to the cell changes at this residue to the function of the resulting gap junctions composed of or were not cell that were with or were with Neither nor to the 20 have on the of connexins in and human W.L. Common J.E. Kelsell D.P. Cell Commun. Adhes. 2001; 8: 415-418Google Scholar, J.A. Paul D.L. Dev. Dyn. Scholar, A. J. Cell Sci. 1998; Scholar, A. C. Willecke K. Traub O. Eur. J. Cell Biol. 65: Scholar, H. Willecke K. Eur. J. Cell Biol. Scholar, D. E. S. S. E. P. P. J. Investig. Dermatol. 103: Google Scholar, A. P. D. J. Investig. Dermatol. 2000; Scholar). these in the and of Cx family members in the of the (16Di W.L. Rugg E.L. Leigh I.M. Kelsell D.P. J. Investig. Dermatol. 2001; 117: 958-964Google protein of at least Cx26, Cx30, Cx32, Cx43, and and of and in human Cx26 is from skin and is to and D. E. S. S. E. P. P. J. Investig. Dermatol. 103: Google Scholar). that Cx26 is in the differentiation that in to different as the A. J. Cell Sci. 1998; Scholar, D. P. D. J. Investig. Dermatol. 1998; Scholar, R. R. Hodgins M.B. J. Investig. Dermatol. 1999; Scholar, E. D. P. of 1997; Scholar, J.A. Paul D.L. Mol. Biol. Cell. 1995; Scholar). Cx26 of a D. C. A. Traub O. E. Willecke K. J. Cell Biol. 1998; these are not for skin differentiation and with loss-of-function mutations in Cx26 but from hearing loss and a of skin that vary in severity D.P. W.L. M.J. Am. J. Hum. Genet. 2001; Scholar, Res. Res. Rev. 2000; Scholar, P.M. T.W. Harris 1999; 103: Scholar). Mutations in Cx26 are responsible for a of human autosomal dominant and recessive hearing loss R. P. Hum. 2000; Scholar, P.M. E. Res. Res. Rev. 2000; Scholar). Cx26 is to the and cells and is thought to function by and within the for function of cells Res. Res. Rev. 2000; Scholar). a mouse of Cx26 in the that these have hearing loss that was with of cells M. M. Wu P. Willecke K. C. Biol. 2002; Scholar). and G. R. Brown K. S. S. M. D. Hodgins M. Hum. Mol. Genet. have the first mouse Cx26 and that the of mutations that are responsible for deafness R. P. Hum. 2000; Scholar, P.M. E. Res. Res. Rev. 2000; and the of in the of these that Cx26 is not for differentiation. for and differentiation of the skin in the of functional Cx26 is that other Cxs co-expressed by for the loss of This the important of specific mutations in Cx26 in the of both deafness and skin disease. by the D66H mutation sensorineural deafness as well as and and other including with (18Maestrini E. Korge B.P. Ocana-Sierra J. Calzolari E. Cambiaghi S. Scudder P.M. Hovnanian A. Monaco A.P. Munro C.S. Hum. Mol. Genet. 1999; 8: 1237-1243Google Scholar). G59A mutation a and sensorineural deafness (22Heathcote K. Syrris P. Carter N.D. Patton M.A. J. Med. Genet. 2000; 37: 50-51Google Scholar). by W.L. Common J.E. Kelsell D.P. Cell Commun. Adhes. 2001; 8: 415-418Google that D66H was retained within expressed in cells and retained D66H was also in in D66H G. R. Brown K. S. S. M. D. Hodgins M. Hum. Mol. Genet. Scholar). the of this D.L. A. Hum. Mol. Genet. that D66H and G59A mutations were both retained in a D66H exerted a dominant-negative effect on Cx26 but not Cx30, whereas G59A a dominant-negative effect on but not on wild-type Cx26 D.L. A. Hum. Mol. Genet. Scholar). from these in that D66H was retained a population of G59A was to be transported to the cell surface and a of gap In as be both D66H and G59A exerted dominant-negative effects on wild-type examined mutants in different cell including cells as used by the that G59A was transported to the cell surface in to cell type D.L. A. Hum. Mol. Genet. Scholar). is that a population of Cx26 expressed in in both G59A not functional gap junctions and trans-dominant In examined the of D66H and was retained within the not functional gap junction channels. It is that with wild-type Cx26, Cx30, and Cx32, but not Cx43, to the transport of the D66H and gap junction plaques at the cell surface. heteromeric channels composed of Cx32 and Cx26 have been well J. Biol. Chem. 1995; Scholar, S. J.A. Biochem. J. 1999; Scholar), that the of D66H mutants to the cell surface is by heteromeric with wild-type is that the D66H mutation in Cx26 the for and with wild-type Cx26 this This of cells D66H-GFP with and to D66H-GFP transport to the cell surface. We were to that D66H-GFP a to and is that D66H-GFP is within the a not associated with of protein D66H-GFP is not to or is within a within the first extracellular loop of Cx26, and this of the Cx is to be in J. Scholar, Proc. Natl. Acad. Sci. U. S. A. Scholar), T.W. R. J. 1996; as well as the of Cxs connexons M. Nicholson B.J. Biol. 1996; Scholar). functional of this within the first extracellular loop of Cx26 was further by the that the at and the at are critical for the of a functional gap junction channel A. K. S. Y. J. Biol. Chem. Scholar). of D66H within the and transport to the cell surface co-expressed with wild-type Cxs that the D66H may to or expressed is that a at is and a to a at this the of this to Cx or in which more mutations at were this may be the D66H and were retained within the whereas and formed gap junctions at the cell surface. is that a from a negative to a at with or within the D66H and are retained within that more is that of gap junctions were formed by and permeability to fluorescent was suggesting that this residue is not only important for transport and of Cx26 but also a in connexon and the function of the gap junction the from to a resulting in only the addition of a small to the residue a effect on the function of the suggesting this is a critical and important Cx the D66H a population of the G59A was transported to the cell surface and gap junctions that were to by a of G59A-GFP compared with wild-type which may this also transport properties as by and D.L. A. Hum. Mol. Genet. Scholar). that is within the motif which is suggested to a reverse Nicholson B.J. J. Cell. Biol. 1998; Scholar), the of with the more this and (22Heathcote K. Syrris P. Carter N.D. Patton M.A. J. Med. Genet. 2000; 37: 50-51Google Scholar). a population of G59A the the resulting channels were D66H and G59A were to a dominant-negative effect on wild-type Cx26 channel function. with Cx26 to D66H transport to the cell gap junction channel function was These that formed from of wild-type and D66H mutants are This effect deafness is the that the D66H mutation channel whereas the G59A retained a of channel the D66H mutation a more (22Heathcote K. Syrris P. Carter N.D. Patton M.A. J. Med. Genet. 2000; 37: 50-51Google Scholar). but not exerted a trans-dominant effect on Cx32 function. This may the of and specific within the first extracellular loop in Cx with (23Rouan F. White T.W. Brown N. Taylor A.M. Lucke T.W. Paul D.L. Munro C.S. Uitto J. Hodgins M.B. Richard G. J. Cell Sci. 2001; 114: 2105-2113Google Scholar), D66H was to a small effect on Cx43 channel function in the of changes in the subcellular of Cx43 or the D66H In G59A was also to a trans-dominant effect on Cx43 function. wild-type Cx43 and Cx26 not heteromeric these trans-dominant negative effects are to is that the within the first extracellular the for the of D66H retained within the may the transport of wild-type Cx43 to the cell resulting in is that the of G59A channels functional Cx43 channels may the overall of direct heteromeric between and wild-type connexins may to be the for the dominant and trans-dominant effects to Cx transport and gap junction In have the localization and function of two Cx26 D66H and of these Cx26 mutants exerted dominant-negative as well as effects on co-expressed wild-type the of these mutants to exhibit both deafness and different of skin disease be on the of the mutants to with other Cx have that residue a in not only Cx26 transport but also in the of a functional gap junction We for in the Cx26 mutants in and for in the We also for of the We are to for

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