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• W1991496811 abstract "White Sponge Nevus (WSN) is a rare, autosomal dominant disorder that predominantly affects noncornified stratified squamous epithelia. Clinically, it is characterized by the presence of soft, white, and ‘‘spongy’’ plaques in the oral mucosa. The characteristic histopathologic features are epithelial thickening, parakeratosis, and vacuolization of the suprabasal layer of oral epithelial keratinocytes. Mutations in keratin 4 (K4) and keratin 13 (K13) genes have already been demonstrated to be responsible for WSN; the identification of new keratin mutations in a stratified squamous epithelia closely related to epidermis is of relevance for the understanding of the biochemistry of intermediate filaments, and for genotype phenotype correlations. In this study we investigated a 27-y-old, female Italian patient, affected by white asymptomatic oral plaques. Sequence analysis revealed a 3 bp (ACA) heterozygous insertion localized in the helix initiation motif of the 1A alpha helical domain of K4. We report this new K4 gene mutation and describe an amino acid insertion, in the 1A domain, responsible for a keratin disease. White Sponge Nevus (WSN) is a rare, autosomal dominant disorder that predominantly affects noncornified stratified squamous epithelia. Clinically, it is characterized by the presence of soft, white, and ‘‘spongy’’ plaques in the oral mucosa. The characteristic histopathologic features are epithelial thickening, parakeratosis, and vacuolization of the suprabasal layer of oral epithelial keratinocytes. Mutations in keratin 4 (K4) and keratin 13 (K13) genes have already been demonstrated to be responsible for WSN; the identification of new keratin mutations in a stratified squamous epithelia closely related to epidermis is of relevance for the understanding of the biochemistry of intermediate filaments, and for genotype phenotype correlations. In this study we investigated a 27-y-old, female Italian patient, affected by white asymptomatic oral plaques. Sequence analysis revealed a 3 bp (ACA) heterozygous insertion localized in the helix initiation motif of the 1A alpha helical domain of K4. We report this new K4 gene mutation and describe an amino acid insertion, in the 1A domain, responsible for a keratin disease. White Sponge Nevus (WSN) of Cannon (OMIM #193900) is a rare, autosomal dominant disorder that predominantly affects noncornified stratified squamous epithelia, such as the oral mucosa and, less frequently, extra oral sites, including the mucosal membrane of the nose, esophagus, rectum, and vulvovaginal mucosa (Metz and Metz, 1979Metz J. Metz G. der Nevus spongiosus albus mucosae-Ubersicht und eigene Beobachtungen.Z Hautkr. 1979; 54: 604-612PubMed Google Scholar;Jorgenson and Levin, 1981Jorgenson R.J. Levin L.S. White sponge nevus.Arch Dermatol. 1981; 117: 73-76Crossref PubMed Scopus (65) Google Scholar). It was first described by Hyde in 1909 (Hyde, 1909Hyde J.N. An unusual naevus of the tongue in a five-year-old boy.J Cutan Dis. 1909; 27: 256Google Scholar), but the term ‘‘White Sponge Nevus’’ was coined in 1935 byCannon, 1935Cannon A.B. White sponge nevus of the mucosa (nevus spongiosus albus mucosa).Arch Dermatol Syphilol. 1935; 31: 365-370Crossref Scopus (67) Google Scholar. The disease is characterized by a wide variability and high penetrance, but with a benign clinical decourse. Clinically, WSN is characterized by the presence of bilateral, soft, white, and ‘‘spongy’’ plaques of the oral mucosa. The surface of the plaque is thick, folded, and may peel away from the underlying tissue. The expression of WSN is variable, the size of the plaques varies from patient to patient, different areas of the oral mucosa can be affected, and their distribution can change with time in the same patient. The buccal mucosa is the most commonly affected site, followed by the labial mucosa, the alveolar ridges, and the floor of the mouth. The onset of WSN usually occurs before 20 y of age and often in early childhood (Jorgenson and Levin, 1981Jorgenson R.J. Levin L.S. White sponge nevus.Arch Dermatol. 1981; 117: 73-76Crossref PubMed Scopus (65) Google Scholar;Nichols et al., 1990Nichols G.E. Cooper P.H. Underwood P.B. Kenneth E.G. White Sponge Nevus.Obstetrics Gynaecol. 1990; 76: 545-548PubMed Google Scholar). The characteristic histopathologic features are epithelial thickening, parakeratosis, and vacuolization of the suprabasal layer of epithelial keratinocytes. Compact aggregates of keratin intermediate filaments are visible in the upper spinous layer (Frithiof and Banoczy, 1976Frithiof L. Banoczy J. White sponge nevus (leukoedema exfoliativum mucosae oris): Ultrastructural observations.Oral Surg. 1976; 41: 607-622Abstract Full Text PDF Scopus (34) Google Scholar;Morris et al., 1988Morris R. Gansler T.S. Rudisill M.T. Neville B. White Sponge Nevus diagnosis by light microscopic and ultrastructural cytology.Acta Cytol. 1988; 32: 357-361PubMed Google Scholar) and resemble those found in epidermal disorders associated with keratin defects (McLean and Lane, 1995McLean W.H.I. Lane E.B. Intermediate filaments in disease.Curr Opin Cell Biol. 1995; 7: 118-125Crossref PubMed Scopus (209) Google Scholar;Corden and McLean, 1996Corden L.D. McLean W.H.I. Human keratin diseases. Hereditary fragility of specific epithelial tissues.Exp Dermatol. 1996; 5: 297-307Crossref PubMed Scopus (186) Google Scholar). Keratins are a family of about 30 proteins ranging in size from 40 to 67 kDa, forming the keratin intermediate filaments (KIF) network in the epidermal keratinocytes. Keratin genes are clustered in two chromosomal loci, type I (acidic) keratins (from keratin 9 to keratin 20) are localized on chromosome 17 (17q21), with the exception of keratin 18 that maps to chromosome 12; whereas type II (basic) keratins (from keratin 1 to keratin 8) are clustered on chromosome 12 (12q13). Keratins consist of a central rod domain with four alpha helical segments (1A, 1B, 2A, and 2B) separated by short nonhelical linker sequences (L1, L12, and L2) and flanked by nonhelical, globular sequences (V1 and V2 and H1, H2 in type II only). Assembly of KIF begins with the dimerization of two keratin molecules, forming a two chained coiled-coil heterodimer (type I/type II). These heterodimers assemble to finally form the filament (Steinert et al., 1993aSteinert P.M. Marekov L.N. Fraser R.D. Parry D.A. Keratin intermediate filament structure. Crosslinking studies yield quantitative information on molecular dimensions and mechanism of assembly.J Mol Biol. 1993; 20: 436-452Crossref Scopus (232) Google Scholar;Parry and Steinert, 1995Parry D. Steinert P.M. Intermediate Filament Structure. 1995Google Scholar). Based on experimental results, several models of keratin alignment have been proposed. The most accepted model is an end-to-end overlap between the end of the 2B domain segment (helix termination motif) of one molecule and the beginning of the 1A segment (helix initiation motif) of the other one (Coulombe and Fuchs, 1990Coulombe P.A. Fuchs E. Elucidating the early stages of keratin filament assembly.J Cell Biol. 1990; 111: 153-169Crossref PubMed Scopus (188) Google Scholar;Hatzfeld and Weber, 1990Hatzfeld M. Weber K. The coiled coil of in vitro assembled keratin filaments is a heterodimer of type I and II keratins: use of site-specific mutagenesis and recombinant protein expression.Cell Biol. 1990; 110: 1199-1210Crossref PubMed Scopus (190) Google Scholar;Steinert et al., 1993bSteinert P.M. Yang J.M. Bale S.J. Compton J.G. Concurrence between the molecular overlap regions in keratin intermediate filaments and the locations of keratin mutations in genodermatoses.Biochem Biophys Res Commun. 1993; 197: 840-848Crossref PubMed Scopus (74) Google Scholar). Keratins are differentially expressed during epidermal differentiation (Polakowska and Haake, 1994Polakowska R.R. Haake A.R. Apoptosis: the skin from a new perspective.Cell Death Differ. 1994; 1: 19-31PubMed Google Scholar), in a stratum-specific and tissue-specific manner (Eckert and Welter, 1996Eckert R.L. Welter J.F. Epidermal keratinocytes – genes and their regulation.Cell Death Differ. 1996; 3: 373-383PubMed Google Scholar). For example, cells of the basal epidermis express keratin 5 and keratin 14 that are downregulated and replaced by keratin 1, keratin 10, and keratin 2e in suprabasal keratinocytes of the truncal epidermis (Korge and Krieg, 1996Korge B.P. Krieg T. The molecular basis for inherited bullous diseases.J Mol Med. 1996; 74: 59-70Crossref PubMed Scopus (45) Google Scholar;Irvine and McLean, 1999Irvine A.D. McLean W.H. Human keratin diseases: the increasing spectrum of disease and subtlety of the phenotype-genotype correlation.Br J Dermatol. 1999; 140: 815-828Crossref PubMed Scopus (322) Google Scholar). Suprabasal keratinocytes of the buccal, nasal, esophageal mucosae, and anogenital epithelia specifically express K13 and K4 (Romano et al., 1992Romano V. Raimondi E. Bosco P. et al.Chromosomal mapping of human cytokeratin 13 gene (KRT13).Genomics. 1992; 14: 495-497Crossref PubMed Scopus (15) Google Scholar;Mischke et al., 1990Mischke D. Wille G. Wild A.G. Allele frequencies and segregation of human polymorphic keratins K4 and K5.Am J Hum Genet. 1990; 46: 548-552PubMed Google Scholar), and mutations in K4 and K13 genes have been associated with WSN (De Mostaccioli et al., 1997De Mostaccioli S. Laurenzi V. Terrinoni A. Richard G. Didona B. Cavalieri R. Melino G. White Sponge Nevus is caused by mutations in mucosal keratins.Eur J Dermatol. 1997; 7: 405-408Google Scholar;Rugg et al., 1995Rugg E.L. McLean W.H.I. Allison W.E. et al.A mutation in the mucosal keratin K4 is associated with oral white sponge nevus.Nat Genet. 1995; 11: 450-452Crossref PubMed Scopus (107) Google Scholar;De Mostaccioli et al., 1997De Mostaccioli S. Laurenzi V. Terrinoni A. Richard G. Didona B. Cavalieri R. Melino G. White Sponge Nevus is caused by mutations in mucosal keratins.Eur J Dermatol. 1997; 7: 405-408Google Scholar). Up to now only a substitution in K13 (L15P;De Mostaccioli et al., 1997De Mostaccioli S. Laurenzi V. Terrinoni A. Richard G. Didona B. Cavalieri R. Melino G. White Sponge Nevus is caused by mutations in mucosal keratins.Eur J Dermatol. 1997; 7: 405-408Google Scholar) and a deletion in K4 (ΔN8 or ΔN9;Rugg et al., 1995Rugg E.L. McLean W.H.I. Allison W.E. et al.A mutation in the mucosal keratin K4 is associated with oral white sponge nevus.Nat Genet. 1995; 11: 450-452Crossref PubMed Scopus (107) Google Scholar) have been described in this disease, both being localized in the 1A alpha-helical domain. In this study we report a new K4 gene mutation in WSN, which is the first to involve an amino acid insertion, also within the helix initiation motif. Biopsy samples of the proband were taken and processed for light and electron microscopy. Ethical approval and patient consent were obtained before proceeding with the diagnostic skin biopsy. Electron microscopy samples were prefixed with 2% (wt/vol) glutaraldehyde for 2 h at 4°C; complete fixation was achieved by incubation with 1% (wt/vol) osmium tetroxide in 0.1 M cacodylate buffer, 4.5% (wt/vol) sucrose for 1 h at 4°C. Samples were dehydrated in ethanol and embedded in epoxy resin. Semithin sections (1 μm) of embedded samples were cut using a microtome and stained with uranyl acetate 1% (wt/vol). Light microscopy samples were embedded in paraffin and stained with hematoxylin and eosin. Genomic DNA samples were extracted from patient blood and from the other family members according to standard procedures (Sambrook et al., 1989Sambrook J. Fritsch E.F. Maniatis T. Molecular Cloning.A Laboratory Manual. 1989; Vol. 1-2-3Google Scholar) A 3 mm skin biopsy was taken from the mouth lateral mucosa, total RNA was extracted with Qiagen RNAeasy mini kit (Hilden, Germany) and used in the reverse transcriptase-polymerase chain reaction (RT-PCR) reaction. RT-PCR reactions were performed using the RT-PCR one step system (Life Technologies, Paisley, U.K.), with 100 ng of total RNA and 0.4 μM of each forward and reverse primers; buffer and enzyme concentrations were according to the manufacturer instructions. The entire coding region of the K4 gene was reverse transcribed and amplified using primers K4FA 5′-TGCAGCCAT- GATTGCCAGACAG-3′, for (+) strand and K4R5 5′-CTGGACACA- GTGAGCTGCAG-3′, for (–) strand, designed from the published cDNA sequences (accession #X97566 and #AF066051). PCR fragments were resolved on 0.8% agarose gel (TAE), extracted and purified using the Qiaex II extraction kit (Qiagen). Approximately 100 ng of purified template DNA was automatically sequenced with the BigDye Termination Reaction Kit (Perkin Elmer, Branchburg, NJ) on an ABI-PRISM 377 DNA sequencer (Perkin Elmer). Primers K4F1(+) 5′-CAGGAGGTCACCATCAACCAG-3′ and K4R1(–) 5′-CTCAAGGTTTTTGCTGGAGG-3′ were used to detect and confirm the mutation. Reverse transcription and amplification of K13 mRNA was performed using primers K13FA 5′-CCTGTCATCCAATCCTGCTCTCA-3′ for (+) strand and K13RC2 5′-GTCGACGCTTCCTGCTGAGG-3′ for (–) strand, designed from the published sequences (accession #X14640, #M27908, and #AF049259). In this study, we investigated a 27-y-old, female Italian patient, affected by white asymptomatic oral plaques. The lesions had a bilateral distribution and were limited to the buccal and labial mucosa (Figure 1a); no abnormalities were found in the nasal, laryngeal, anal, and vaginal mucosa. The presence in the patient’s family of other affected members was consistent with an autosomal dominant transmitted disorder (Figure 2a). The histologic examination of a skin biopsy taken from the lateral buccal mucosa revealed a marked hyperplasia and parakeratotic hyperkeratosis of the suprabasal epithelial layers. Intracellular edema and vacuolization, with a small accumulation of keratohyaline granules were also visible (Figure 1b). Ultrastructural examination showed marked tonofilaments aggregates (Figure 1c) in cells of the upper spinous layer; these aggregates were often accumulated in the cell periphery, leaving a perinuclear electron-lucent zone (Figure 1d). These findings, together with the absence of involvement of other body sites, are consistent with a keratin defect and confirmed the diagnosis of WSN.Figure 2Pedigree and mutation analysis of the WSN family studied. (A) Pedigree, (B) mutation analysis. The cDNA obtained from buccal skin biopsy of the proband (II-1) and from genomic DNA of his relatives (I-1, I-2, II-2) are shown. The asterisks indicate the point of the ACA triplet insertion, after this point the sequence becomes scrambled due to the presence of the two different alleles.View Large Image Figure ViewerDownload (PPT) The most probable candidate genes responsible for the disease were the K13 and the K4 genes. In order to study these two genes, we amplified and directly sequenced their entire coding region. Sequence analysis, using sense and antisense primers, revealed a 3 bp (ACA) heterozygous insertion (Figure 2b,II-1) localized in the 1A domain of the K4 gene, between bp 458 and bp 459 from the ATG (asterisks in Figure 2b). The 3 bp insertion results in the addition of a glutamine residue between the second and third amino acid of the 1A rod alpha-helical domain of K4. Thus, the sequence changes from GAA(E).CAG(Q) to GAA(E).CAA(Q).CAG(Q) (the bases and the amino acids inserted are underlined). The mutation was confirmed by cloning and sequencing the mutated allele. No other mutations were detected in the proband in the remaining coding region of the K4 gene and in the entire coding region of K13 gene. In order to demonstrate that this is the disease-causing mutation, we performed a sequence analysis on genomic DNA of the 1A domain of K4 for the parents (Figure 2b; I-2, II-1, II-1, II-2). We detected the heterozygous insertion in all affected family members, whereas the mutation was missing in the nonaffected father (Figure 2b,I-1). The mutation is presumably due to an ectopic crossing over during the meiosis of gametogenesis. Up to now, only one K4 mutation, also localized in the 1A domain, has been reported for this disease (Rugg et al., 1995Rugg E.L. McLean W.H.I. Allison W.E. et al.A mutation in the mucosal keratin K4 is associated with oral white sponge nevus.Nat Genet. 1995; 11: 450-452Crossref PubMed Scopus (107) Google Scholar). This mutation is a deletion of an asparagine residue that is highly conserved in type II keratins. Interestingly, the deletion of the same residue was found in Keratin 6a, in a case of Pachyonychia Congenita type I (Bowden et al., 1995Bowden P.E. Haley J.L. Kansky A. Rothnagel J.A. Jones D.O. Turner R.J. Mutation of a type II keratin gene (k6a) in pachyonichia congenita.Nat Genet. 1995; 10: 363-365Crossref PubMed Scopus (204) Google Scholar). In agreement with these previous studies, our results demonstrate that a deletion or an insertion of an amino acid in this specific part of the 1A domain can result in a lateral shift of the first residues involved in the 1A alpha helix initiation motif and thus disrupt alpha-helical domain stability (Letai et al., 1993Letai A. Coulombe P.A. McCormick M.B. Yu Q.C. Hutton E. Fuchs E. Disease severity correlates with position of keratin point mutations in patients with epidermolysis bullosa simplex.Proc Natn Acad Sci USA. 1993; 90: 3197-3201Crossref PubMed Scopus (113) Google Scholar), type I/type II keratin pairing and assembly of KIF (Steinert et al., 1993aSteinert P.M. Marekov L.N. Fraser R.D. Parry D.A. Keratin intermediate filament structure. Crosslinking studies yield quantitative information on molecular dimensions and mechanism of assembly.J Mol Biol. 1993; 20: 436-452Crossref Scopus (232) Google Scholar;Steinert, 1995Steinert P.M. A model for hierarchical structure of the human epidermal cornified cell envelope.Cell Death Differ. 2. Cold Spring Harbor Laboratory Press, New York1995: 33-40Google Scholar). In our case the resulting clinical phenotype is mild, because the patient shows involvement of only part of the buccal mucosa (Figure 1a), whereas the other mucosae expressing K4 are normal, suggesting that in these sites this mutation is better tolerated. In this study we have reported a new K4 gene mutation in a familial case of WSN and, for the first time, have described an amino acid insertion, in the 1A domain, responsible for a keratin disease. Insertion/deletion mutations of keratin genes are very rare (Chen et al., 1993Chen M.A. Bonifas J.M. Matsumura K. Blumenfeld A. Epstein Jr, Eh A novel three-nucleotide deletion in the helix 2B region of keratin 14 in epidermolysis bullosa simplex: delta E375.Hum Mol Genet November. 1993; 2: 1971-1972Crossref PubMed Scopus (45) Google Scholar;Bowden et al., 1995Bowden P.E. Haley J.L. Kansky A. Rothnagel J.A. Jones D.O. Turner R.J. Mutation of a type II keratin gene (k6a) in pachyonichia congenita.Nat Genet. 1995; 10: 363-365Crossref PubMed Scopus (204) Google Scholar;Rugg et al., 1995Rugg E.L. McLean W.H.I. Allison W.E. et al.A mutation in the mucosal keratin K4 is associated with oral white sponge nevus.Nat Genet. 1995; 11: 450-452Crossref PubMed Scopus (107) Google Scholar;Coleman et al., 1999Coleman C.M. Munro C.S. Smith F.J.D. Uitto J. McLean W.H.I. Epidermolytic palmoplantar Keratoderma due to a novel type of keratin mutation, a 3-bp insertion in the keratin 9 helix temination motif.Br J Dermatol. 1999; 140: 815-828Crossref PubMed Scopus (38) Google Scholar). Therefore their identification in diseases affecting the epidermis or closely related epithelia is of general interest to investigators studying KIF related disorders. More work needs to be done in order to understand how the different keratin mutations cause diseases and why the resulting phenotypes are so variable. In particular, the identification of amino acid insertions or deletions may be very useful for future structure-function studies. This work was carried out thanks to MURST-40%, Telethon grants #E872, #417/BI and grant AIRC 1998, to Gerry Melino." @default.
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• W1991496811 title "A Glutamine Insertion in the 1A Alpha Helical Domain of the Keratin 4 Gene in a Familial Case of White Sponge Nevus" @default.
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