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• W2040441467 abstract "To the Editor: Keratin 1 (K1) is one of the major keratins expressed in differentiating epidermal keratinocytes. Pathogenic mutations in the K1 gene, KRT1, have been demonstrated to underlie several distinct disorders of keratinization, such as epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma) and nonepidermolytic, diffuse palmoplantar keratoderma (PPK) (for review seeIshida-Yamamoto et al., 2002Ishida-Yamamoto A. Takahashi H. Iizuka H. Lessons from disorders of epidermal differentiation-associated keratins.Histol Histopathol. 2002; 17: 331-338PubMed Google Scholar). Recently, we have identified a heterozygous frameshift mutation in KRT1 (1609–1610delGGinsA) in a multigenerational family with ichthyosis hystrix Curth–Macklin (IHCM, OMIM 146590) (Sprecher et al., 2001Sprecher E. Ishida-Yamamoto A. Becker O.M. et al.Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.J Invest Dermatol. 2001; 116: 511-519Crossref PubMed Scopus (95) Google Scholar). IHCM is a rare autosomal dominant skin disorder characterized by extensive (nonepidermolytic) hyperkeratosis that involves in some families (Ollendorff Curth and Macklin, 1954Ollendorff Curth H. Macklin M.T. The genetic basis of various types of ichthyosis in a family group.Am J Hum Genet. 1954; 6: 371-382PubMed Google Scholar;Sprecher et al., 2001Sprecher E. Ishida-Yamamoto A. Becker O.M. et al.Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.J Invest Dermatol. 2001; 116: 511-519Crossref PubMed Scopus (95) Google Scholar) predominantly palms and soles, although skin over large joints and the trunk may also be affected. The hyperkeratosis may initially show a striate pattern but often is diffuse, leading to severe flexural contractures, fissures, and sometimes loss of digits. IHCM is characterized by specific ultrastructural abnormalities of the cytoskeleton of suprabasal keratinocytes, including an entangled meshwork of individual keratin intermediate filaments (KIF), which aggregate in cytoplasmic shells instead of forming KIF bundles, perinuclear vacuolization, and the presence of binucleated cells (Anton-Lamprecht et al., 1973Anton-Lamprecht I. Ollendorff-Curth H. Schnyder U.W. Ultrastructure of inborn errors of keratinization. II. Ichthyosis hystrix type Curth–Macklin.Arch Forsch. 1973; 246: 77-91Crossref PubMed Scopus (20) Google Scholar;Niemi et al., 1990Niemi K.M. Virtanen I. Kanerva L. Muttilainen M. Altered keratin expression in ichthyosis hystrix Curth–Macklin. A light and electron microscopic study.Arch Dermatol Res. 1990; 282: 227-233Crossref PubMed Scopus (24) Google Scholar;Anton-Lamprecht, 1994Anton-Lamprecht I. Ultrastructural identification of basic abnormalities as clues to genetic disorders of the epidermis.J Invest Dermatol. 1994; 103: 6S-12SCrossref PubMed Scopus (55) Google Scholar;Sprecher et al., 2001Sprecher E. Ishida-Yamamoto A. Becker O.M. et al.Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.J Invest Dermatol. 2001; 116: 511-519Crossref PubMed Scopus (95) Google Scholar). The mutation 1609–1610delGGinsA, which occurred in a region encoding the variable tail domain (V2) of K1, was shown to replace most of the wild-type carboxy-terminal sequence, including the structurally and functionally important glycine loop motifs of K1, with an aberrant and truncated peptide of 76 residues. Interestingly, another heterozygous frameshift mutation in KRT1 (1628delG) at almost the same location was detected in a family with autosomal dominant striate palmoplantar keratoderma (SPPK, OMIM 148700) (Whittock et al., 2002Whittock N.V. Smith F.J. Wan H. et al.Frameshift mutation in the V2 domain of human keratin 1 results in striate palmoplantar keratoderma.J Invest Dermatol. 2002; 118: 838-844Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). The predicted molecular consequences of this single nucleotide deletion were comparable with those observed in IHCM, including replacement of the carboxy-terminal glycine-rich V2 tail with a novel, alanine-rich and shorter peptide. Nonetheless, clinical features and underlying ultrastructural abnormalities differed. The hyperkeratosis in SPPK was distributed in a linear or plaque-like pattern, was limited to palms and soles, and much less severe than in IHCM. Electron microscopy revealed only slightly decreased electron density of KIF but attenuation of desmosomal midline structures as well as the outer desmosomal plaques where KIF are inserted (Whittock et al., 2002Whittock N.V. Smith F.J. Wan H. et al.Frameshift mutation in the V2 domain of human keratin 1 results in striate palmoplantar keratoderma.J Invest Dermatol. 2002; 118: 838-844Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). These features broadly overlap with those observed in SPPK due to mutations in genes encoding the major desmosomal proteins, desmoplakin and desmoglein 1, which presumably led to haploinsufficiency of the faulty proteins (Armstrong et al., 1999Armstrong D.K.B. McKenna K.E. Purkis P.E. Green K.J. Eady R.A.J. Leigh I.M. Hughes A.E. Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma.Hum Mol Genet. 1999; 8: 143-148Crossref PubMed Scopus (209) Google Scholar;Rickman et al., 1999Rickman L. Simrak D. Stevens H.P. et al.N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma.Hum Mol Genet. 1999; 8: 971-976Crossref PubMed Scopus (172) Google Scholar;Whittock et al., 1999Whittock N.V. Ashton G.H.S. Dopping-Hepenstal P.J.C. Gratian M.J. Keane Eady R.A.J. McGrath J.A. Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency.J Invest Dermatol. 1999; 113: 940-946Crossref PubMed Scopus (113) Google Scholar;Hunt et al., 2001Hunt D.M. Rickman L. Whittock N.V. et al.Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma.Eur J Hum Genet. 2001; 9: 197-203Crossref PubMed Scopus (84) Google Scholar). To investigate possible pathomechanisms for either KRT1 mutation,Whittock et al., 2002Whittock N.V. Smith F.J. Wan H. et al.Frameshift mutation in the V2 domain of human keratin 1 results in striate palmoplantar keratoderma.J Invest Dermatol. 2002; 118: 838-844Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar performed in vitro transfections with four mutant K1(mK1)-GFP constructs, including the mutants causing IHCM and SPPK. In contrast to wild-type K1 (wtK1) with typical filamentous, cytoplasmic distribution, all tested mutants showed partial nuclear localization, although their newly gained V2 sequences did not contain potential nuclear localization signals. As a similar faulty K1 distribution was also observed for K1 variants truncated before or within the V2 domain, it was proposed that nuclear accumulation of mK1-GFP is attributable to the loss of the wild-type V2 tail domain. To evaluate the biologic relevance of these observations in vivo, we assessed in this study the distribution pattern of mK1 as well as the desmosomal ultrastructure in skin samples of a patient with IHCM by immunohistochemistry and immunoelectron microscopy. We raised a polyclonal rabbit antibody (mK1) against a peptide of 14 amino acids corresponding to the carboxy-terminal end of mK1 anchored by a cysteine (C/LAAGALAAGALEAP) (Ishida-Yamamoto et al., 2000Ishida-Yamamoto A. Kato H. Kiyama H. et al.Mutant loricrin is not crosslinked into the cornified cell envelope but is translocated into the nucleus in loricrin keratoderma.J Invest Dermatol. 2000; 115: 1088-1094Crossref PubMed Scopus (31) Google Scholar). Cornified cells obtained from skin scrapings of an affected individual with IHCM carrying mutation 1609–1610delGGinsA (Sprecher et al., 2001Sprecher E. Ishida-Yamamoto A. Becker O.M. et al.Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.J Invest Dermatol. 2001; 116: 511-519Crossref PubMed Scopus (95) Google Scholar) and an unaffected control individual were processed for immunoblotting (Ishida-Yamamoto et al., 2000Ishida-Yamamoto A. Kato H. Kiyama H. et al.Mutant loricrin is not crosslinked into the cornified cell envelope but is translocated into the nucleus in loricrin keratoderma.J Invest Dermatol. 2000; 115: 1088-1094Crossref PubMed Scopus (31) Google Scholar). A specific band of 60 kDa corresponding to the mK1 polypeptide, which is 32 amino acids shorter than wtK1 (molecular weight 65494), was detected in the patient sample but not in the control (Fig 1a). Immunohistochemistry was performed on a skin biopsy sample of hyperkeratotic sole skin (Fig 1b–e). In contrast to control skin, mK1 staining was observed from just above the basal cells throughout all layers of the epidermis, including the stratum corneum. Immunofluorescence analysis revealed extensive colocalization of wtK1 and mK1 in the cytoplasm, but neither protein was detected within the nuclei (Fig 1e). Using antibodies against mK1, wtK1, and desmoglein 1 for immunoelectron microscopy, we confirmed the coexpression of mK1 and wtK1 polypeptides in cytoplasmic KIF (Fig 1f) and association of mK1-positive KIF with the desmosomal plaques (Fig 1h), whereas again no nuclear accumulation of mK1 was observed (Fig 1i). The mK1 and wtK1 positive KIF network appeared abnormal and not bundled (Fig 1f,h,i), differing from thick bundles (tonofibrils) labeled only with wtK1 in the normal control skin (Fig 1g). KIF in the basal cells of the patient were normal. In contrast to SPPK, the ultrastructure of desmosomal plaques as well as the expression of desmoglein 1 and desmoplakin did not reveal any abnormalities in IHCM (Fig 2). Specifically, inner plaques and midlines of desmosomes in keratinocytes expressing mK1 were well developed and indistinguishable from a normal control (Fig 2i,j).Figure 2Desmosomes in IHCM. Cryo-ultramicrotome sections were stained with antibodies against desmoglein 1 (a,b: Dsg1-P23) and desmoplakin (c,d: desmoplakin multiepitope cocktail, American Research Products, Belmont, MA), and detected with secondary antibodies coupled to fluorescein isothiocyanate (DAKO, Glostrup, Denmark). Postembedding immunoelectron microscopy of desmoglein 1 (e,g) and cryo-ultramicrotomy staining of desmoplakin. (f,h) Ten nanometer gold-conjugated secondary antibodies were used. (i,j) Transmission electron microscopy pictures of desmosomes in the superficial epidermis (Sprecher et al., 2001Sprecher E. Ishida-Yamamoto A. Becker O.M. et al.Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.J Invest Dermatol. 2001; 116: 511-519Crossref PubMed Scopus (95) Google Scholar). Inner plaques and midlines of desmosomes are marked with arrowheads and arrows, respectively. Patient skin (a,c,e,f,i) and normal sole skin (b,d,g,h,j). Scale bars: (a–d) 0.01 mm; (e–j) 100 nm.View Large Image Figure ViewerDownload (PPT) This study, together with the detection of mK1 by MALDI-TOF mass spectroscopy (Sprecher et al., 2001Sprecher E. Ishida-Yamamoto A. Becker O.M. et al.Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.J Invest Dermatol. 2001; 116: 511-519Crossref PubMed Scopus (95) Google Scholar), unequivocally demonstrate that the predicted mK1 allele leading to IHCM is indeed expressed in vivo and not subjected to non-sense-mediated mRNA decay (Frischmeyer and Dietz, 1999Frischmeyer P.A. Dietz H.C. Nonsense-mediated mRNA decay in health and disease.Hum Mol Genet. 1999; 8: 1893-1900Crossref PubMed Scopus (812) Google Scholar). The broad colocalization of mK1 and wtK1 also indicates a normal site- and differentiation-specific expression profile of mK1. Considering the abnormal organization of KIF that contain mK1 and their accumulation in shell-like cytoplasmic structures, our observations strongly suggest that this K1 mutant interferes with KIF bundling, possibly in a dominant negative fashion, thus perturbing the KIF cytoskeleton. Our results, however, do not confirm the previously reported in vitro data showing nuclear localization of mK1-GFP (Whittock et al., 2002Whittock N.V. Smith F.J. Wan H. et al.Frameshift mutation in the V2 domain of human keratin 1 results in striate palmoplantar keratoderma.J Invest Dermatol. 2002; 118: 838-844Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). The specific mechanisms leading to trapping and accumulation of mK1-GFP in the nuclei remain unclear. There has been no report showing nuclear localization of keratin proteins in vivo. Although the wtK1 construct distributed normally in the transfected cells, the coupled GFP may additionally impair the distribution of mK1 and may therefore lead to the abnormal nuclear localization. Alternatively, a disproportional high expression of K1 constructs could cause aberrant keratin localization. In either case, our data suggest that nuclear keratins do not to play an important part for the disease pathology in the affected skin tissue. Finally, normal desmosome formation in IHCM suggests that the cytopathologic effects leading to hyperkeratosis and PPK in this disorder differ from those in SPPK, and may be related to abnormalities in supramolecular KIF organization and cytoplasmic trafficking of insoluble proteins, such as loricrin, as previously suggested (Sprecher et al., 2001Sprecher E. Ishida-Yamamoto A. Becker O.M. et al.Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.J Invest Dermatol. 2001; 116: 511-519Crossref PubMed Scopus (95) Google Scholar). It is also possible that mK1 impacts upon shapes of the cells and integrity of other cellular structures, such as organelles and the nucleus, as the cells are often binucleated and the granular cells are not flattened (Anton-Lamprecht et al., 1973Anton-Lamprecht I. Ollendorff-Curth H. Schnyder U.W. Ultrastructure of inborn errors of keratinization. II. Ichthyosis hystrix type Curth–Macklin.Arch Forsch. 1973; 246: 77-91Crossref PubMed Scopus (20) Google Scholar;Niemi et al., 1990Niemi K.M. Virtanen I. Kanerva L. Muttilainen M. Altered keratin expression in ichthyosis hystrix Curth–Macklin. A light and electron microscopic study.Arch Dermatol Res. 1990; 282: 227-233Crossref PubMed Scopus (24) Google Scholar;Anton-Lamprecht, 1994Anton-Lamprecht I. Ultrastructural identification of basic abnormalities as clues to genetic disorders of the epidermis.J Invest Dermatol. 1994; 103: 6S-12SCrossref PubMed Scopus (55) Google Scholar;Sprecher et al., 2001Sprecher E. Ishida-Yamamoto A. Becker O.M. et al.Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix.J Invest Dermatol. 2001; 116: 511-519Crossref PubMed Scopus (95) Google Scholar). This may lead to gross alteration in the overall structures of the epidermis. The reasons for the apparent clinical and ultrastructural differences between IHCM and SPPK despite the similarities of the mK1 products in both disorders are not clear at present. Possible explanations could be slight differences in the length of the abnormal tail domains, expression of other type II keratins that might compensate for abnormal K1 functions, or local factors, such as traumatization due to body weight or manual labor. Future studies of additional families with different mutations in keratin tail domains or transgenic animals expressing this type of mutations might help to clarify and understand these questions further. We would like to thank Drs Takuji Masunaga and Akira Ishiko (Keio University School of Medicine, Tokyo, Japan) for advice on cryo-ultramicrotomy techniques, and Miss Yasuyo Nishinome for her excellent technical assistance. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare of Japan to A.I-Y and NIH grants K08-AR02141 and P01-AR38239 to GR. The electron microscopy samples were observed at the Electron Microscopy Unit, Central Laboratory for Research and Education, Asahikawa Medical College." @default.
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• W2040441467 title "In Vivo Studies of Mutant Keratin 1 in Ichthyosis Hystrix Curth–Macklin" @default.
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