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Genetic Evidence for a Novel Human Desmosomal Cadherin, Desmoglein 4

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Genetic Evidence for a Novel Human Desmosomal Cadherin, Desmoglein 4 View metadata, citation and similar papers at core.ac.uk brought to you by CORE PRIORITYprovided by PUBLICATIONElsevier - Publisher Connector See related Commentary on page ix Genetic Evidence for a Novel Human Desmosomal Cadherin, Desmoglein 4 Neil V.Whittock1 and Christopher Bower2 1Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, United Kingdom, 2Department of Dermatology, Royal Devon and Exeter Hospital, Exeter, United Kingdom Desmosomes are essential adhesion structures in most bp that encodes a precursor protein of 1040 amino acids. epithelia that link the intermediate ¢lament network of The predicted mature protein comprises 991 amino one cell to its neighbor, thereby forming a strong bond. acids with a molecular weight of 107822 Da at pI 4.38. The molecular components of desmosomes belong to Human desmoglein 4 shares 41% identity with human the cadherin superfamily, the plakin family, and the ar- desmoglein 1, 37% with human desmoglein 2, and 50% madillo repeat protein family.The desmosomal cadher- with human desmoglein 3.Analysis of the exon/intron ins are calcium-dependent transmembrane adhesion organization of the human desmoglein 4 gene (DSG4) molecules and comprise the desmogleins and desmo- demonstrates that it is composed of 16 exons spanning collins.To date, three human desmoglein isoforms have approximately 37 kb of 18q12 and is situated between been characterized, namely desmogleins 1, 2, and 3 that DSG1 and DSG3.We have demonstrated using are expressed in a tissue- and di¡erentiation-speci¢c RT-PCR on multiple tissue cDNA samples that desmo- manner.Here we have identi¢ed and characterized, at glein 4 has very speci¢c tissue expression in salivary the genetic level, a novel human desmoglein cDNA gland, testis, prostate, and skin. Keywords: Desmosome/ sharing homology with desmogleins 1, 2, 3 and we gene organization /desmosomopathy/pemphigus. J Invest Der- name this desmoglein 4.The human desmoglein 4 matol120:523 ^530, 2003 cDNA (3.6 kb) contains an open reading frame of 3120 esmosomes are disc-like structures of 0.1^0.5 mmin dent class of single pass transmembrane cell adhesion molecules, diameter and are located principally in epithelial the cadherins (Nilles et al, 1991) and were subsequently named cells where they play a major role in cell-cell adhe- ‘‘desmosomal cadherins’’. sion as well as cell communication (Garrod, 1993; Similar to the classical cadherins, the desmosomal cadherins Kouklis et al, 1994; Garrod, 1996; Green and Jones, possess ¢ve homologous extracellular domains containing puta- D1996). Viewed under standard transmission electron microscopy tive calcium-binding sites, a single transmembrane spanning do- desmosomes present with a distinctive ultrastructure consisting main, and a carboxy-terminal cytoplasmic tail (Wheeler et al, of two major domains. The ¢rst, termed the extracellular core 1991). The cytoplasmic tails of the desmogleins and desmocollins domain or ‘‘desmoglea’’, is approximately 30 nm in width and is contain many motifs including an intracellular anchor domain separated by an electron-dense mid line region. This extracellular (IA), an intracellular cadherin-typical segment (ICS) and a major core domain consists of the extracellular heads of the desmoso- binding site that contributes to the binding of the desmosomal mal cadherins that provide cellular adhesion to neighboring cells plaque protein, plakoglobin (Schmidt et al, 1994). The desmocol- (North et al, 1999). The second domain consists of an electron- lins exist in ‘‘a’’and ‘‘b’’ isoforms, the shorter ‘‘b’’ isoform lacking dense cytoplasmic plaque that can be further separated into an the major binding site that eliminates its ability to bind plakoglo- outer dense plaque and an inner dense plaque, which are sepa- bin (Troyanovsky et al, 1993; Troyanovsky et al, 1994a; Troyanovs- rated from one another by an electron lucent zone. The cytoplas- ky et al, 1994b). In addition, molecules in the desmoglein micplaque is composed of the desmosomal plaque proteins subgroup contain a unique carboxy-terminal extension contain- desmoplakin, plakoglobin, the plakophilins and the amino ter- ing a ‘‘repeat unit domain’’ (RUD) that comprises a repeating minal domains of the intermediate ¢lament proteins. Early stu- motif of approximately 29 amino acids (Koch et al, 1990; Wheeler dies on desmosomes identi¢ed a group of glycoproteins and et al, 1991) that is predicted to form b-strands. In order to avoid evidence suggested that they mediated the speci¢c recognition confusion the nomenclature was simpli¢ed by renaming the hu- and adhesion functions of desmosomes (Cohen et al, 1983). With man proteins such that there were six desmocollins (i.e., 1a, 1b, 2a, the resulting isolation and characterization of these glycoproteins 2b, 3a, and 3b), and three desmogleins (i.e., 1, 2, and 3) (Buxton it was demonstrated that they were related to the calcium depen- et al,1993). The largest desmosomal cadherins are desmocollin 2 and des- moglein 2; they are the essential desmosomal cadherins common Manuscript received November 15, 2002; revised December 1, 2002; to all desmosome-possessing tissues, including simple epithelia, accepted for publication December 9, 2002 myocardium and many cell cultures (Koch et al, 1992; Theis et al, Reprint requests to: Dr. Neil V Whittock, Molecular Genetics Labora- tory, Old Pathology Building, Royal Devon and Exeter Hospital, Barrack 1993; Schmidt et al, 1994). In contrast, the epidermal isoforms Road, Exeter, United Kingdom, EX2 5DW. E-mail: nwhittoc@hgmp. desmocollins 1 and 3, and desmogleins 1 and 3 are restricted to mrc.ac.uk specialized epithelia, mostly strati¢ed squamous ones (Koch et al, 0022-202X/03/$15.00 . Copyright r 2003 by The Society for Investigative Dermatology, Inc. 523 524 WHITTOCK AND BOWER THE JOURNAL OF INVESTIGATIVE DERMATOLOGY 1992; Schafer et al, 1994; Schmidt et al, 1994; Schafer et al,1996). an ABI 377 geneticanalyzer (Applied Biosystems) and analyzed using Within the epidermis the three desmocollin/glein isoforms are Sequence Navigator 1.0.1. software (Applied Biosystems). To determine expressed in a di¡erentiation-speci¢c manner, with desmocollin the expression of desmoglein 4 a multiple tissue RNA panel II (adult) 2 and desmoglein 2 being basal, desmoglein 3 and desmocollin (BD Clontech, Basingstoke, UK) was reverse transcribed and ampli¢ed as 3 being basal layer and ¢rst suprabasal layer, and desmoglein 1 described above. and desmocollin 1 being upper spinous and granular layer of epi- RACE PCR The 50 and 30 ends of the desmoglein 4 cDNA were dermis (Arnemann et al,1993;Kinget al, 1993; Theis et al, 1993; isolated from skin and testis total RNA using the Smart Race Schmidt et al,1994;Kinget al, 1995; Nuber et al,1995;Yueet al, ampli¢cation kit (BD Clontech) according to the manufacturer’s 1995; Adams et al, 1998; Denning et al, 1998). In addition to its role instructions. Primers used to amplify the 50 and 30 ends of desmoglein 4 in cell adhesion in deep strati¢ed squamous epithelia, desmoglein were EX1B RACE 50 -CTG AAG AAG AGC CAA TCC ATT CCT TTG GG-30, and 3UTRRACEA 50 -GCA TCC CTT GAT ACT GTC TAA 3 is also critical in anchoring the telogen hair to the outer root 0 sheath of the hair follicle and thus demonstrates that desmosomes CGA ATA GC-3 . RACE PCR was performed using the Advantage II PCR kit (BD Clontech) according to the manufacturer’s instructions, and are important in maintaining the normal structure and function PCR products were puri¢ed and sequenced as above. of the hair (Koch et al,1998). The human desmoglein genes comprise either 15 or 16 exons (Silos et al, 1996; Frank et al,2001;Huntet al, 2001) that are clus- RESULTS tered within a region of approximately 150 kb in the order 50 - DSG1-DSG3-DSG2-30 (Simrak et al, 1995). The human desmo- Sequence analysis reveals a novel human desmosomal collin genes comprise 17 exons (Whittock et al, 2000b; Cserhal- cadherin Analysis of the annotated human genome data mi-Friedman et al, 2001), where exon 16 is alternatively spliced, (http://genome.ucsc.edu) for chromosome 18 demonstrated giving rise to the ‘‘a’’ and ‘‘b’’ forms of the protein (Collins et al, several predicted genes in the 100 kb gap between DSG1 1991; Greenwood et al, 1997). However, the genomicorganization and DSG3 using various algorithms. These included of the desmocollin genes is closer to that of the classical cadherins ENST00000308128 (Ensembl), chr18.29.005.a and chr18.30.001.a than the desmogleins (Greenwood et al, 1997). The entire DSC/ (Twinscan), and NT_010966.11 (Genescan). All of these predicted DSG gene complex occupies approximately 700 kb on 18q12.1, genes demonstrated varying levels of homology with the known and the genes are arranged in the order cen-30 -DSC3-DSC2- desmoglein genes, DSG1-3. In addition, the predicted mRNA’s DSC1-50 -50 -DSG1-DSG3-DSG2-30tel, where the two gene clus- and proteins showed a high level of homology to desmogleins ters are transcribed outward from the interlocus region (Arnemann 1^3. However, it was clear based on exon size conservation with et al, 1991; King et al, 1993; Cowley et al,1997;Huntet al, 1999). other DSG genes and amino acid sequence that the gene Desmosome integrity is critical for normal cell-cell adhesion. prediction algorithms had incorrectly identi¢ed several exons This is clearly highlighted in a group of disorders whereby de- and most importantly had not correctly identi¢ed exon 1 and its fects occur within desmosomal proteins that lead to the loss of associated promoter. In order to locate exon 1, ¢ve regions this adhesion. The geneticdiseases of desmosomes cover a range containing high homology with the syntenic mouse region of disorders that can be inherited in autosomal dominant or re- were identi¢ed as HumMus.18.14374, 14379, 14381, 14382, and cessive modes and that can range from a¡ecting just palmoplantar 14383.
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