Desmosomes and Hemidesmosomes: Constitutive Molecular Components

Schwarz, Michaela; Owaribe, Katsushi; Kartenbeck, Jürgen; Franke, Werner W.

doi:10.1146/annurev.cb.06.110190.002333

Cited by 276 publications

(122 citation statements)

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“…It is thought that heterophilic interactions between these two types of transmembrane glycoproteins establish desmosome-mediated cell-cell adhesion (Schwarz et al 1990;Garrod et al 2002a,b;. Another extracellular component with a less well-defined function is corneodesmosin (CDSN) (Simon et al , 2001).…”

Section: Resultsmentioning

confidence: 99%

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Yang

Liang²,

Koch³

et al. 2004

Genes Dev.

103

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Netherton syndrome (NS) is a human autosomal recessive skin disease caused by mutations in the SPINK5 gene, which encodes the putative proteinase inhibitor LEKTI. We have generated a transgenic mouse line with an insertional mutation that inactivated the mouse SPINK5 ortholog. Mutant mice exhibit fragile stratum corneum and perinatal death due to dehydration. Our analysis suggests that the phenotype is a consequence of desmosomal fragility associated with premature proteolysis of corneodesmosin, an extracellular desmosomal component. Our mouse mutant provides a model system for molecular studies of desmosomal stability and keratinocyte adhesion, and for designing therapeutic strategies to treat NS.Supplemental material is available at http://www.genesdev.org.Received June 17, 2004; revised version accepted August 6, 2004. Netherton Syndrome (NS) (MIM 256500) is a severe, recessively inherited skin disease in humans with high neonatal lethality. It is characterized by ichthyosiform erythroderma, atopic dermatitis, bamboo hair, skin barrier defects, and elevated IgE levels in survivors (Krafchik and Toole 1983;Judge et al. 1994). Mutations have been identified in the SPINK5 (serine proteinase inhibitor Kazal type 5) gene of NS patients (Chavanas et al. 2000;Sprecher et al. 2001;Walley et al. 2001;Bitoun et al. 2002;Komatsu et al. 2002). SPINK5 encodes LEKTI (lympho-epithelial Kazal-type-related inhibitor), which is a putative proteinase inhibitor that contains an N-terminal signal peptide and 15 domains with high internal homology (Magert et al. 1999). Each domain has four conserved cysteines. Domains 2 and 15 possess two additional cysteines, which make them typical Kazal-type proteinase inhibitor domains (Magert et al. 1999). LEKTI exhibits proteinase inhibitor activity in vitro (Magert et al. 1999;Komatsu et al. 2002;Walden et al. 2002;Mitsudo et al. 2003). In NS patients, loss or reduction of LEKTI activity is presumed to result in elevated proteolytic activity in the suprabasal epidermis, leading to erythroderma and skin-barrier defects. However, the specific proteins that are targeted for degradation in these patients have not been identified. We describe here a Spink5 mutant mouse line that shows severe skin defects associated with desmosomal fragility, and thus, provides insights into the molecular pathogenesis of NS and a novel model system for studies of keratinocyte adhesion. Results and DiscussionTransgenic mouse line OVE1498 was generated by coinjection of a tyrosinase-tagged (Yokoyama et al. 1990) Sleeping Beauty transposon (Ivics et al. 1997) (termed pT-Tybs-3ЈE) along with PGK2-SB10 (Ivics et al. 1997) (see Supplementary Fig. S1) into inbred FVB/N embryos. The transgenic founder and its transgenic F1 offspring were phenotypically normal and showed no evidence for transposition of the transgene(s) (data not shown). When transgenic F1 mice were intercrossed, ∼25% of the newborn offspring developed severe skin blistering and water barrier defects, leading to death within several hours after birth ...

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Section: Resultsmentioning

confidence: 99%

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Yang

Liang²,

Koch³

et al. 2004

Genes Dev.

103

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“…43 There are four related members of the desmoglein family, each with a separate gene localized to chromosome 18p. Desmoglein-2, encoded by DSG2, is highly expressed in cardiac tissue, making it an attractive ARVD/C candidate gene.…”

Section: Desmoglein-2mentioning

confidence: 99%

Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy

2008

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SUMMARYArrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy estimated to affect approximately 1 in 5,000 individuals. Cardinal manifestations include right ventricular enlargement and dysfunction, fibrofatty replacement of myocytes in the right ventricle, characteristic electrocardiographic abnormalities, and ventricular arrhythmia most commonly arising from the right ventricle. The disease is frequently familial and typically involves autosomal dominant transmission with low penetrance and variable expressivity. Approximately 50% of symptomatic individuals harbor a mutation in one of the five major components of the cardiac desmosome. Nevertheless, other genetic modifiers and environmental factors complicate the clinical management of mutation carriers as well as counseling of their relatives. This Review summarizes the known genetic mutations associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy, describes possible origins of recurrent mutations, presents theories on the pathogenesis of disease following a mutation, and discusses the current issues surrounding clinical use of genetic analysis in the assessment of individuals with this condition.

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“…Desmosomes form a major class of adhesive junctions found especially in epithelial tissues, where adjacent cells are linked together by well-defined plaques situated on the plasma membrane [1,2]. Internally, the plaques are associated with the intermediate filament network extending from cell to cell.…”

Section: Introductionmentioning

confidence: 99%

Visualisation by electron microscopy of the unique part of the cytoplasmic domain of a desmoglein, a cadherin‐like protein of the desmosome type of cell junction

Rutman¹,

Buxton²,

Burdett³

1994

FEBS Letters

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Part of the cytoplasmic domain of a human desmoglein, Dsgl, a cadherin-like protein found in desmosomes of epithelial cells, has been visualised by electron microscopy. The cloned fragment contains five repeats of a 29 + 4 residue sequence unique to desmogleins, followed by a glycine-rich region. In rotary shadowed preparations the molecule consists of a globular head attached to a thin tail, the latter perhaps corresponding to the glycine-rich region. This portion of the molecule is thought to span the width of the inner dense plaque. The structure and dimensions concur well to the configuration deduced from the protein sequence.

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Desmosomes and Hemidesmosomes: Constitutive Molecular Components

Cited by 276 publications

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Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy

Visualisation by electron microscopy of the unique part of the cytoplasmic domain of a desmoglein, a cadherin‐like protein of the desmosome type of cell junction

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Desmosomes and Hemidesmosomes: Constitutive Molecular Components

Cited by 276 publications

References 0 publications

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice

Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy

Visualisation by electron microscopy of the unique part of the cytoplasmic domain of a desmoglein, a cadherin‐like protein of the desmosome type of cell junction

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Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice