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Minireview
Closing the Gap on Autosomal Dominant Connexin-26 and Connexin-43 Mutants Linked to Human Disease*
From the Departments of Anatomy & Cell Biology and Physiology & Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada
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ABSTRACT |
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TOP
ABSTRACT
Overview of Connexin-linked...Cells within the vast majority of human tissues communicate directly through clustered arrays of intercellular channels called gap junctions. Gene ablation studies in mouse models have revealed that these intercellular channels are necessary for a variety of organ functions and that some of these genes are essential for survival. Molecular genetics has uncovered that germ line mutations in nearly half of the genes that encode the 21-member connexin family of gap junction proteins are linked to one or more human diseases. Frequently, these mutations are autosomal recessive, whereas in other cases, autosomal dominant mutations manifest as disease. Given the broad and overlapping distribution of connexins in a wide arrangement of tissues, it is hard to predict where connexin-linked diseases will clinically manifest. For instance, the most prevalent connexin in the human body is connexin-43 (Cx43), yet autosomal dominant mutations in the GJA1 gene, which encodes Cx43, exhibit modest developmental disorders resulting in a disease termed oculodentodigital dysplasia. Autosomal recessive mutations in the gene encoding Cx26 result in moderate to severe sensorineural hearing loss, whereas autosomal dominant mutations produce hearing loss and a wide range of skin diseases, including palmoplantar keratoderma. Here, we will focus on autosomal dominant mutations of the genes encoding Cx26 and Cx43 in relation to models that link genotypes to phenotypic outcomes with particular reference to how these approaches provide insight into human disease.
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Overview of Connexin-linked Diseases |
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A little over a decade ago, the first mutations in the gene encoding Cx322 were found to be linked to the X-linked form of Charcot-Marie-Tooth disease (1–3). Now, numerous mutations in the gene encoding Cx32 have been linked to this neuropathy associated with the demyelination of peripheral axons (4). Once it was established that connexin gene mutations could lead to disease, this brought in a new era of connexin studies that included the structure and function analysis of disease-linked mutants. Mutations in the gene encoding Cx47 have been attributed to Pelizaeus-Merzbacher-like disease, which is another disease characterized by defective myelination (5, 6). Sensory organ diseases, including congenital cataracts, have been attributed to mutations in the genes encoding Cx46 and Cx50 (7), whereas moderate to severe sensorineural hearing loss has been assigned to mutations in upwards of five different connexin family members, including Cx26, Cx30, Cx30.3, Cx31, and Cx43 (8–10). Interestingly, mutations in Cx26 alone are thought to account for 35–45% of all congenital sensorineural hearing loss in some populations (8). The same subset of connexin family members linked to sensorineural hearing loss is, in some cases, responsible for a wide array of skin diseases (11–13). Until ODDD was linked to mutations in the GJA1 gene encoding Cx43 (14), it was expected that germ line mutations in this connexin would likely be lethal given the critical role Cx43 plays in cardiac function and its widespread expression in >35 distinct tissue environments (15, 16). In addition to reports linking connexin gene germ line mutations to disease, other studies have suggested that somatic mutations in the gene encoding Cx40 may be linked to atrial fibrillation (17), and recently, polymorphisms in Cx50 have been proposed to be linked to schizophrenia (18). These latter associations need to be interpreted cautiously and will likely require the study of large cohorts of patients before they can unequivocally be considered causal of human disease.
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Autosomal Dominant Mutations |
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Once molecular geneticists had identified mutations in the genes encoding connexins and linked these results to a cohort of patients, these findings inevitability led to the need for a rigorous set of studies to establish how these genotypic changes lead to disease outcomes. This process is particularly intriguing when considering autosomal dominant mutants, in which both wild-type and mutant proteins are predicted to be produced in equal quantities in all cells where the promoter is temporally and spatially activated. Notably, not only do these molecular studies provide reference points to understanding the manifestations of the disease but offer tremendous potential to assign functional importance to specific domains and motifs that house the mutation. In fact, the use of disease-causing Cx43 mutants provides an experimental setting that cannot be recapitulated by gene ablation or replacement approaches. Although deletion of a connexin gene (knock-out) or substitution of one connexin gene for another (knock-in) in the mouse is an excellent means to define the essential properties of a specific connexin, it does not provide a realistic representation of connexins in human health and disease, where patients rarely suffer from a condition in which a connexin is ablated. The closest comparison with connexin ablation is found in a few cases in which the connexin gene harbors a nucleotide duplication or deletion resulting in a severe truncation or deletion of the protein (19, 20).
There are at least 14 autosomal dominant mutations resulting in 10 amino acid substitutions or deletion sites in the GJB2 gene encoding Cx26 linked to conditions of moderate to severe hearing loss and skin diseases that include Vohwinkel syndrome, keratitis-ichthyosis- deafness syndrome, hystrix-like ichthyosis-deafness syndrome, Bart-Pumphrey syndrome, and palmoplantar keratodermas (12). Only seven autosomal dominant mutations have been associated with hearing loss without the added skin disease burden. Thus, the autosomal dominant nature of these mutations tends to be syndromic, whereas >100 recessive mutations in the same gene typically manifest as sensorineural hearing loss only (12). Thus, one could argue that a mixed background of wild-type and mutant proteins increases the spectrum of disease load if not the severity of the disease. There are 39 autosomal dominant mutations in the GJA1 gene encoding Cx43 (Fig. 1A) (16) with the resulting disease outcome being classified as ODDD highlighted by developmental defects in the craniofacial bones around the eyes and nose, loss of enamel resulting in early destruction of the teeth, and lack of soft tissue separation of two or three digits (14). In addition to these commonly found developmental disorders, patients often exhibit an assortment of conditions that range broadly from neurological to cardiac disorders (14, 21–24). It is possible that epigenetic effects may also contribute to these disease states. Interestingly, in cases in which the patient harbors a frameshift mutation (fs230 (24) or fs260 (25)) resulting in a gross deletion of the C terminus of Cx43, these individuals have an increased disease load of palmoplantar keratodermas or palmar hyperkeratosis not unlike what is found in some patients harboring dominant GJB2 mutations. The fact that one point mutation in Cx43 (L11P) (26) has been associated with hyperkeratosis suggests that the added disease load in the skin is not restricted solely to the events linked to the C terminus of the molecule.
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Expression of Cx26 and Cx43 Mutants in Reference Cell Lines |
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A common approach to assess any new family or class of disease-linked mutants is to express cDNA constructs that encode the mutant protein in reference cell models that lack endogenous connexins and compare their localization and functional properties with their wild-type counterparts. Over half of the autosomal dominant Cx26 mutants (27–29) and
10 Cx43 mutants (30–33) have been assessed using this basic approach and found to exhibit two distinct subcellular localization profiles. First, the vast majority of mutants reach the cell surface and assemble into gap junction-like structures as assessed by light microscopy. Based on combinations of dye transfer and electrophysiological measurements, these same mutants either are incapable of forming functional gap junction channels in gap junctional intercellular communication-deficient reference cells or form channels that function poorly in comparison with their wild-type counterparts. The general interpretation of these types of mutants is that their ability to traffic to the cell surface is retained, but they suffer from improper folding or oligomerization resulting in the permanent closing or near complete closure of the gap junction pore. Although channel malformation is the most common feature of Cx26 and Cx43 mutants, a second class of mutants (e.g. Cx26D66H (27) and Cx43fs260 (25)) exhibit protein trafficking defects. In the case of the D66H mutant, it may still retain the capacity to reach the cell surface but fail to stabilize and return to the trans-Golgi network, where it is most prevalent (29). On the other hand, the fs260 mutant appears to have difficulty in passing quality control mechanisms associated with the endoplasmic reticulum (Fig. 1, B and C) (30). Not surprisingly, there are also a few mutants that exhibit intermediate properties of being able to reach the cell surface and assemble into gap junction-like structures with relatively poor efficiency (32). |
Dominant and trans-Dominant Cx26 and Cx43 Mutants |
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When both mutant and wild-type connexin counterparts are coexpressed within the same cell, the obvious question raised is whether these species will intermix and, if so, does the mutant kill the function of the wild-type connexin or does the wild-type connexin rescue the function of the mutant. Clear evidence for mutant and wild-type Cx43 co-mixing in some state of oligomerization was recently provided by co-immunoprecipitation experiments in which differentially tagged wild-type and mutant (G21R and G138R) Cx43 proteins were found to interact (34). Although this relationship is likely to occur among many if not most of the autosomal dominant Cx43 and Cx26 mutants, this principle has yet to be widely demonstrated. However, coexpression studies in which wild-type Cx26 or Cx43 was coexpressed with various mutant counterparts have repeatedly demonstrated that the mutants typically inhibit the function of their wild-type counterparts (28, 29). However, this interpretation needs to be carefully assessed, as mutant connexins are often overexpressed in relationship to their wild-type connexin proteins. Attempts to overcome this limitation have involved coexpressing equal quantities of cDNAs encoding differentially fluorescent protein-tagged wild-type and mutant counterparts and assessing the intensity of red and green fluorescent proteins found at gap junction plaques (34). Using this more elaborate approach, both the G21R and G138R mutants were found to be dominant-negative to Cx43 even when predicted to be expressed at a 1:1 molar ratio. In addition, these two mutants exhibited different potency levels, suggesting that not all mutants are likely to be equally effective in inhibiting the function of wild-type Cx43 (34).
Given that many autosomal dominant Cx26 mutants and a couple of Cx43 mutants are syndromic, it was speculated that one or more of these mutants may have trans-dominant effects on other members of the connexin family. The rationale for this possibility is built on the fact that connexins can co-oligomerize with other members of the connexin family in vivo to form a variety of heteromeric connexon arrangements. For example, it is reasonable to predict that Cx26 mutants might directly interact with coexpressed Cx32 because both wild-type Cx32 and Cx26 form heteromeric arrangements (35). Functional analysis in which Cx26 mutants were coexpressed with Cx32 revealed that the mutants were dominant to this connexin (28, 29). The mechanism of this effect still remains speculative, but because keratinocytes may express upwards of nine different connexin family members, selective mutant-connexin interactions may result in a broader shutdown of overall gap junctional intercellular function, causing skin abnormalities.
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Organotypic Reference Models |
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Although basic two-dimensional reference culture cellular systems can provide insights into how mutants are expressed and managed within a defined cellular system, they do not recapitulate the complexity of cell-cell interactions and signaling that occur in three-dimensional organoids or organotypic cultures. Because autosomal dominant Cx26 and Cx43 mutants cause clinically detectable skin phenotypes, expressing these mutants in undifferentiated keratinocytes and inducing the differentiation and stratification of the skin offer a potential advantage. To that end, both Cx26 and Cx43 mutants have been expressed in rat keratinocytes, and their differentiation into an organotypic epidermis has been assessed for architectural defects in generating normal vital and cornified cell layers as well as for the ability to express molecular markers indicative of keratinocyte differentiation (36–38). Intriguing studies have revealed that several Cx26 and Cx43 mutants that are known to cause hyperkeratosis and other skin defects failed to cause any notable changes in the architecture or differentiation of organotypic epidermis (Fig. 1, D and E). It is notable that these mutants typically manifest their effects in the thick skin of the palms and soles of patients, raising the possibility that an epidermal phenotype will not recapitulate in organoid cultures unless exposed to mechanical friction. In addition, it is possible that organotypic cultures fail to satisfactorily recapitulate human epidermis and that more sophisticated approaches involving primary human keratinocytes are required. Thus, the generation of mouse models of human diseases may prove to be necessary to examine Cx26 and Cx43 mutant effects on organ development, differentiation, and susceptibility to disease.
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Mouse Models of Connexin Disease |
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In 2003, Hodgins and co-workers (39) reported on the first mouse model of a human connexin disease. In this seminal study, the authors engineered a mouse that expressed the Cx26D66H mutant driven by the keratin-10 promoter and that exhibited the mild to moderate sensorineural hearing loss and Vohwinkel syndrome (39). This mouse was viable and, notably, exhibited the hallmark keratoderma characteristics of patients that harbor this mutation and suffer from Vohwinkel syndrome. Recently, a mutant mouse model of erythrokeratodermia variabilis caused by a Cx31F137L mutant was generated and characterized (40). Interestingly, although this mutant mouse model recapitulated the genotype of this autosomal dominant mutant, the hallmark characteristics of hyperproliferation of the stratum germinativum found in humans was not widely evident in these mice. These findings suggest that the genotype/phenotype relationships observed in human connexin-linked diseases may not be re-established identically in mouse models, reflecting distinct differences between mice and humans. For example, Cx43 and Cx26 exhibit distinct spatial expression profiles within the mouse thin epidermal vital layer in comparison with the thicker vital layer found in human skin.
In another study, a mouse was generated by N-ethyl-N-nitrosourea mutagenesis that carried a mutation in the gene encoding Cx43 that resulted in Gly60 being substituted with serine (Cx43G60S; designated as the Gja1Jrt/+ mouse) (41). Although this mutation has not been identified within the human population, these animals were characterized to exhibit syndactyly in the front and hind limbs (Fig. 1F), craniofacial anomalies, and loss of enamel, very similar to the most prominent developmental anomalies found in ODDD patients. In essence, this random mutagenesis screen had fortuitously generated a mouse model of ODDD. At the molecular level, these mice exhibited dramatically reduced Cx43 levels and dysregulated gap junction assembly in many tissues, including the heart, ovaries, and skin (Fig. 1G), with a preference for the loss of the most phosphorylated species of Cx43, which are associated with Cx43 assembly into gap junction plaques (36, 41). Moreover, when the functional status of Cx43 was assessed in these animals, it was found to be operating at <20% normal capacity, highlighting the fact that the mutant protein was dominant to the coexpressed wild-type connexin even though both are predicted to be translated at identical or similar levels (41).
In a more recent study, Fishman and co-workers (42) engineered a mutant mouse to express a known human ODDD-linked I130T mutant. Intriguingly, this mutant mouse exhibited syndactyly, as described for the Gja1Jrt/+ mouse, as well as molecular characteristics that included aberrant Cx43 phosphorylation and trafficking, leading to reduced intercellular junctional conductance (42). Consequently, both mouse models appeared to reliably mimic the human ODDD disease phenotype at least with regard to morphological features. However, although the Cx43I130T mutant mice exhibited no obvious morphological defects of the heart, these animals showed a tendency toward spontaneous and inducible ventricular tachyarrhythmias (42), whereas incidents of bradycardia, bone weaknesses, and hematopoietic defects were seen in the Cx43G60S mice (41). Interestingly, these latter defects are rarely reported in the small cohort of human ODDD patients, raising some concerns that these conditions may be more mouse-specific. However, it will be interesting to determine whether these mouse models can be used to provide clues as to what subclinical disease may be present in the human ODDD patient population that typically remains undetected but may manifest during injury or additional synergistic disease burden. For instance, the Cx43G60S mice become increasingly neutropenic with age, raising the question as to whether ODDD patients become increasingly immunosuppressed in their senior years. At the molecular level, the question remains as to whether the massive decrease in phosphorylated Cx43, seen in both reference mouse models, would also exist in ODDD patients. In mice, it appears that functional Cx43 can be reduced to a fraction of its normal complement in a wide array of tissues before abnormalities become apparent, arguing for Cx43 being produced at considerably higher levels than essential for most organ function. Moreover, given the critical role of Cx43 in cardiac function, it remains to be determined whether ODDD patients are more at risk for spontaneous heart failure, as observed in some mutant mice. This hypothesis will take some time to test owing in large part to the fact that the reported instances of ODDD in the human population to date are in the hundreds. It is possible that as a larger cohort of patients is identified, these types of studies will become more feasible.
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Conclusions and Future Perspectives |
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The discovery of autosomal dominant connexin gene mutations linked to human diseases has further raised the profile of connexins in health and disease. The fact that single amino acid substitutions are potent inhibitors of Cx26 and Cx43 channel function strongly suggests that the majority of the polypeptide motifs of these connexins are essential and intolerant to change. Although it is intriguing to propose that mouse models in which specific mutations leading to coexpression of the mutant and wild-type connexins are engineered into the mouse genome represent the optimal reference model to examine the molecular, cellular, and organ phenotypes of the disease, this may be insufficient due to connexin expressional pattern and regulational differences that exist between mice and humans. To that end, it will continue to be necessary and important to examine the localizational and functional characteristics of connexin mutants in defined and well understood two- and three-dimensional cellular systems. It would also be advantageous to establish cell lines (e.g. fibroblasts and keratinocytes) from ODDD patients in which the biochemical and functional properties of the connexin mutants can be examined in yet another reference model that offers further linkages to the human condition. In the end, meaningful insights into how connexin mutants cause developmental defects or organ failure will likely continue to require the summation of results from multiple reference in vitro and in vivo models.
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FOOTNOTES |
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* This minireview will be reprinted in the 2008 Minireview Compendium, which will be available in January, 2009. This work was supported by the Canadian Institutes of Health Research and the Canada Research Chair Program.
1 To whom correspondence should be addressed. Tel.: 519-661-2111 (ext. 86827); E-mail: dale.laird{at}schulich.uwo.ca.
2 The abbreviations used are: Cx, connexin; ODDD, oculodentodigital dysplasia.
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ACKNOWLEDGMENTS |
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I thank Jared Churko for assistance in preparing Fig. 1; T. Thomas, Q. Shao, S. Langlois, I. Plante, E. McLachlan, C. Lounsbury, and J. Manias for help with the literature search and the data presented in Fig. 1; Drs. G. Kidder and P. Lampe for critical reading of the manuscript; and Dr. J. Rossant and the team at the Toronto Centre for Modeling Human Disease for providing the Gja1Jrt/+ mutant mouse line.
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REFERENCES |
|---|
- Ressot, C., Latour, P., Blanquet-Grossard, F., Sturtz, F., Duthel, S., Battin, J., Corbillon, E., Ollagnon, E., Serville, F., Vandenberghe, A., Dautigny, A., and Pham-Dinh, D. (1996) Hum. Genet. 98, 172–175[CrossRef][Medline] [Order article via Infotrieve]
- Scherer, S. S., Bone, L. J., Deschenes, S. M., Abel, A., Balice-Gordon, R. J., and Fischbeck, K. H. (1999) Novartis Found. Symp. 219, 175–185; Discussion 185–177[Medline] [Order article via Infotrieve]
- Ressot, C., and Bruzzone, R. (2000) Brain Res. Rev. 32, 192–202[CrossRef][Medline] [Order article via Infotrieve]
- Kleopa, K. A., and Scherer, S. S. (2006) Neuromol. Med. 8, 107–122[CrossRef]
- Bugiani, M., Al Shahwan, S., Lamantea, E., Bizzi, A., Bakhsh, E., Moroni, I., Balestrini, M. R., Uziel, G., and Zeviani, M. (2006) Neurology 67, 273–279
[Abstract/Free Full Text] - Orthmann-Murphy, J. L., Enriquez, A. D., Abrams, C. K., and Scherer, S. S. (2007) Mol. Cell. Neurosci. 34, 629–641[CrossRef][Medline] [Order article via Infotrieve]
- Gerido, D. A., and White, T. W. (2004) Biochim. Biophys. Acta 1662, 159–170[Medline] [Order article via Infotrieve]
- Petit, C., Levilliers, J., and Hardelin, J. P. (2001) Annu. Rev. Genet. 35, 589–646[CrossRef][Medline] [Order article via Infotrieve]
- Yang, J. J., Huang, S. H., Chou, K. H., Liao, P. J., Su, C. C., and Li, S. Y. (2007) Audiol. Neurotol. 12, 198–208[CrossRef]
- Liu, X. Z., Xia, X. J., Adams, J., Chen, Z. Y., Welch, K. O., Tekin, M., Ouyang, X. M., Kristiansen, A., Pandya, A., Balkany, T., Arnos, K. S., and Nance, W. E. (2001) Hum. Mol. Genet. 10, 2945–2951
[Abstract/Free Full Text] - Richard, G. (2003) Clin. Exp. Dermatol. 28, 397–409[CrossRef][Medline] [Order article via Infotrieve]
- Richard, G. (2005) Clin. Dermatol. 23, 23–32[Medline] [Order article via Infotrieve]
- van Steensel, M. A. (2004) Am. J. Med. Genet. 131C, 12–19
- Paznekas, W. A., Boyadjiev, S. A., Shapiro, R. E., Daniels, O., Wollnik, B., Keegan, C. E., Innis, J. W., Dinulos, M. B., Christian, C., Hannibal, M. C., and Jabs, E. W. (2003) Am. J. Hum. Genet. 72, 408–418[CrossRef][Medline] [Order article via Infotrieve]
- Laird, D. W. (2005) Biochim. Biophys. Acta 1711, 172–182[Medline] [Order article via Infotrieve]
- Laird, D. W. (2006) Biochem. J. 394, 527–543[CrossRef][Medline] [Order article via Infotrieve]
- Gollob, M. H., Jones, D. L., Krahn, A. D., Danis, L., Gong, X. Q., Shao, Q., Liu, X., Veinot, J. P., Tang, A. S., Stewart, A. F., Tesson, F., Klein, G. J., Yee, R., Skanes, A. C., Guiraudon, G. M., Ebihara, L., and Bai, D. (2006) N. Engl. J. Med. 354, 2677–2688
[Abstract/Free Full Text] - Ni, X., Valente, J., Azevedo, M. H., Pato, M. T., Pato, C. N., and Kennedy, J. L. (2007) J. Med. Genet. 44, 532–536
[Abstract/Free Full Text] - Ainsworth, P. J., Bolton, C. F., Murphy, B. C., Stuart, J. A., and Hahn, A. F. (1998) Hum. Genet. 103, 242–244[CrossRef][Medline] [Order article via Infotrieve]
- Rabionet, R., Lopez-Bigas, N., Arbones, M. L., and Estivill, X. (2002) Trends Mol. Med. 8, 205–212[CrossRef][Medline] [Order article via Infotrieve]
- Loddenkemper, T., Grote, K., Evers, S., Oelerich, M., and Stogbauer, F. (2002) J. Neurol. 249, 584–595[CrossRef][Medline] [Order article via Infotrieve]
- Debeer, P., Van Esch, H., Huysmans, C., Pijkels, E., De Smet, L., Van de Ven, W., Devriendt, K., and Fryns, J. P. (2005) Eur. J. Med. Genet. 48, 377–387[CrossRef][Medline] [Order article via Infotrieve]
- Kjaer, K. W., Hansen, L., Eiberg, H., Leicht, P., Opitz, J. M., and Tommerup, N. (2004) Am. J. Med. Genet. 127A, 152–157
- Vreeburg, M., de Zwart-Storm, E. A., Schouten, M. I., Nellen, R. G., Marcus-Soekarman, D., Devies, M., van Geel, M., and van Steensel, M. A. (2007) Am. J. Med. Genet. 143A, 360–363
- van Steensel, M. A., Spruijt, L., van der Burgt, I., Bladergroen, R. S., Vermeer, M., Steijlen, P. M., and van Geel, M. (2005) Am. J. Med. Genet. 132A, 171–174
- Kelly, S. C., Ratajczak, P., Keller, M., Purcell, S. M., Griffin, T., and Richard, G. (2006) Eur. J. Dermatol. 16, 241–245[Medline] [Order article via Infotrieve]
- Bakirtzis, G., Jamieson, S., Aasen, T., Bryson, S., Forrow, S., Tetley, L., Finbow, M., Greenhalgh, D., and Hodgins, M. (2003) Cell Commun. Adhes. 10, 359–364[Medline] [Order article via Infotrieve]
- Rouan, F., White, T. W., Brown, N., Taylor, A. M., Lucke, T. W., Paul, D. L., Munro, C. S., Uitto, J., Hodgins, M. B., and Richard, G. (2001) J. Cell Sci. 114, 2105–2113
[Abstract/Free Full Text] - Thomas, T., Telford, D., and Laird, D. W. (2004) J. Biol. Chem. 279, 19157–19168
[Abstract/Free Full Text] - Gong, X. Q., Shao, Q., Lounsbury, C. S., Bai, D., and Laird, D. W. (2006) J. Biol. Chem. 281, 31801–31811
[Abstract/Free Full Text] - Roscoe, W., Veitch, G. I., Gong, X. Q., Pellegrino, E., Bai, D., McLachlan, E., Shao, Q., Kidder, G. M., and Laird, D. W. (2005) J. Biol. Chem. 280, 11458–11466
[Abstract/Free Full Text] - Shibayama, J., Paznekas, W., Seki, A., Taffet, S., Jabs, E. W., Delmar, M., and Musa, H. (2005) Circ. Res. 96, e83–e91
[Abstract/Free Full Text] - Lai, A., Le, D.-N., Paznekas, W. A., Gifford, W. D., Jabs, E. W., and Charles, A. C. (2006) J. Cell Sci. 119, 532–541
[Abstract/Free Full Text] - Gong, X. Q., Shao, Q., Langlois, S., Bai, D., and Laird, D. W. (2007) J. Biol. Chem. 282, 19190–19202
[Abstract/Free Full Text] - Stauffer, K. A. (1995) J. Biol. Chem. 270, 6768–6772
[Abstract/Free Full Text] - Langlois, S., Maher, A. C., Manias, J. L., Shao, Q., Kidder, G. M., and Laird, D. W. (2007) J. Biol. Chem. 282, 30171–30180
[Abstract/Free Full Text] - Maher, A. C., Thomas, T., Riley, J. L., Veitch, G., Shao, Q., and Laird, D. W. (2005) Cell Commun. Adhes. 12, 219–230[CrossRef][Medline] [Order article via Infotrieve]
- Thomas, T., Shao, Q., and Laird, D. W. (2007) J. Membr. Biol. 217, 93–104[CrossRef][Medline] [Order article via Infotrieve]
- Bakirtzis, G., Choudhry, R., Aasen, T., Shore, L., Brown, K., Bryson, S., Forrow, S., Tetley, L., Finbow, M., Greenhalgh, D., and Hodgins, M. (2003) Hum. Mol. Genet. 12, 1737–1744
[Abstract/Free Full Text] - Schnichels, M., Worsdorfer, P., Dobrowolski, R., Markopoulos, C., Kretz, M., Schwarz, G., Winterhager, E., and Willecke, K. (2007) Hum. Mol. Genet. 16, 1216–1224
[Abstract/Free Full Text] - Flenniken, A. M., Osborne, L. R., Anderson, N., Ciliberti, N., Fleming, C., Gittens, J. E., Gong, X. Q., Kelsey, L. B., Lounsbury, C., Moreno, L., Nieman, B. J., Peterson, K., Qu, D., Roscoe, W., Shao, Q., Tong, D., Veitch, G. I., Voronina, I., Vukobradovic, I., Wood, G. A., Zhu, Y., Zirngibl, R. A., Aubin, J. E., Bai, D., Bruneau, B. G., Grynpas, M., Henderson, J. E., Henkelman, R. M., McKerlie, C., Sled, J. G., Stanford, W. L., Laird, D. W., Kidder, G. M., Adamson, S. L., and Rossant, J. (2005) Development (Camb.) 132, 4375–4386
[Abstract/Free Full Text] - Kalcheva, N., Qu, J., Sandeep, N., Garcia, L., Zhang, J., Wang, Z., Lampe, P. D., Suadicani, S. O., Spray, D. C., and Fishman, G. I. (2007) Proc. Natl. Acad. Sci. U. S. A. 104, 20512–20516
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