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The Molecular Basis of Keratinizing Disorders

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The Molecular Basis of Keratinizing Disorders Ⅵ Skin Diseases The Molecular Basis of Keratinizing Disorders JMAJ 47(11): 508–513, 2004 Motomu MANABE Professor, Department of Sensory Medicine, Division of Dermatology and Plastic Surgery, Akita University School of Medicine Abstract: Technological advances in molecular biology have brought about a number of major scientific achievements in the field of normal and abnormal epidermal differentiation. This article reviews the molecular defects that cause many types of keratinizing disorders, and highlights the roles of affected genes encoding a variety of epidermal proteins. Key words: Keratinizing disorders; Pathogenic gene; Mutation Introduction Nonbullous ichthyosiform erythroderma is caused by the mutation of the lipoxy- Keratinizing disorders are conditions in genase-3 (ALOXE3) or the 12R-lipoxygenase which qualitative or quantitative abnormality (ALOX12B) gene.1) ALOXE3 and ALOX12B based on a certain genetic background affects are both enzymes involved in the metabolism the pathway of epidermal differentiation from of arachidonic acid. The loss of activity of these the birth of basal cells in the epidermis to their enzymes results in a shortage of essential fatty exfoliation as cornified cells at the skin sur- acids and compromises the hydration ability of face. This paper reviews biological aspects of the horny layer. pathogenic genes encoding cytoskeletal pro- (2) Transglutaminase 1 (TGase 1) teins (keratins), desmosomal proteins (desmo- Lamellar ichthyosis, a condition resembling plakin, desmoglein, plakoglobin, and plako- nonbullous ichthyosiform erythroderma, is philin), gap junction proteins (connexins), caused by the mutation of the TGase 1 gene.2) cornified envelope protein (loricrin), and cer- TGase 1 catalyzes the bridging of proteins at tain enzymes/enzyme inhibitors the ␥-carboxyl groups in glutamine residues and at the lysine residues. Through these Keratinizing Disorders and Pathogenic reactions, TGase 1 bridges the components of the cornified cell envelope, which is a structure Genes (Table 1) that lines the cell membrane, and plays an 1. Enzymes and their inhibitors important role in maintaining the construction (1) Lipoxygenase of cornified cells. In this disease, the activity of This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 129, No. 9, 2003, pages 1414–1418). 508 JMAJ, November 2004—Vol. 47, No. 11 THE MOLECULAR BASIS OF KERATINIZING DISORDERS Table 1 Molecular Basis of Keratinizing Disorders Pathogenic genes Keratinizing disorders Keratins K1 palmoplantar keratoderma Unna-Thost ichthyoisis hystrix Curth-Macklin K1/K10 bullous congenital ichthyosiform erythroderma annular epidermolytic ichthyosis K2e bullous ichthyosis of Siemens K16 focal palmoplantar keratoderma K6a/K16 pachyonychia congenital, type 1 K6b/K17 pachyonychia congenital, type 2 K9 palmoplantar keratoderma Vorner hHa1, hHb1, hHb6 monilethrix Desmosomal proteins desmoglein 1 striate palmoplantar keratoderma desmoplakin striate palmoplantar keratoderma plakoglobin Naxos disease plakophilin skin fragility syndrome Gap junction proteins Connexin 31 Erythrokeratoderma variabilis Connexin 30 Clouston syndrome Connexin 26 Vohwinkel’s syndrome with deafness keratitis-ichthyosis-deafness syndrome Cornified envelope protein loricrin Vohwinkel’s syndrome with ichthyosis progressive symmetric erythrokeratoderma Enzymes and their inhibitors lipoxygenase non-bullous congenital ichthyosiform erythroderma transglutaminase 1 lamellar ichthyosis SERCA 2 Darier disease 3beta-hydroxysteroid dehydrogenase CHILD syndrome cathepsin C Papillon-Lefevre syndrome steroid sulfatase X-linked ichthyosis fatty aldehyde dehydrogenase Sjögren-Larsson syndrome phytanoyl-CoA hydroxylase Refsum disease SPINK5 Netherton syndrome Others SLURP-1 palmoplantar keratoderma Mal de Meleda dyskerin X-linked recessive dyskeratosis congenita telomerase RNA autosomal dominant dyskeratosis congenital Unknown 18q21.3 harlequin fetus 17q25 palmoplantar keratoderma Howel-Evans TGase 1 is reduced, and the ability to bridge spaces, and the decomposition of desmosomes the cornified cell envelope precursor proteins by protease is inhibited. ATPase םis insufficient. As a result, the ceramide that (3) Sarco/endoplasmic reticulum Ca2 normally binds to the cornified cell envelope (SERCA) components is accumulated in intercellular Darrier’s disease is caused by the mutation JMAJ, November 2004—Vol. 47, No. 11 509 M. MANABE ,lesterol sulfate, the substrate for this enzyme -םof the sarco/endoplasmic reticulum Ca2 ATPase type 2 isoform (SERCA2) gene.3) to cholesterol, does not take place, and choles- SERCA2 belongs to the large family of P-type terol sulfate accumulates in the spaces between cation pumps that couple ATP hydrolysis with cornified cells. As a result, cholesterol sulfate cation transport across membranes. SERCA inhibits the activity of chymotrypsin-type serine proteases and hinders the decomposition of םpumps specifically maintain low cytosolic Ca2 .desmosome components םconcentrations by actively transporting Ca2 from the cytosol into the sarco/endoplasmic (7) Fatty aldehyde dehydrogenase (FALDH) reticulum lumen. In this disease, the level of Sjögren-Larsson syndrome is caused by the SERCA2b that has a normal pump function is mutation of the FALDH gene.7) FALDH is a reduced by half, and this results in the impair- component of the fatty alcohol: NAD oxido- mediated signal transduction and reductase enzyme complex that catalyzes the-םment of Ca2 cell adhesion. sequential oxidation of fatty alcohol to alde- (4) 3beta-hydroxysteroid dehydrogenase hyde and fatty acid. In this disease, FALDH CHILD (congenital hemidysplasia with ich- deficiency causes the accumulation of fatty thyosiform erythroderma and limb defects) alcohol and wax esters in the intercellular syndrome is caused by the mutation of the membrane lamella, which may disrupt the 3beta-hydroxysteroid dehydrogenase gene.4) This epidermal water barrier. enzyme functions in the pathway for choles- (8) Phytanoyl-CoA hydroxylase (PAHX) terol biosynthesis. Since cholesterol is impor- Refsum syndrome is caused by the mutation tant in embryonic development controlled by of the PAHX gene.8) PAHX is involved in the the hedgehog signaling pathway, this led to the ␣-oxidation of phytanic acid. In this disease, notion that a cholesterol precursor without the PAHX deficiency leads to the accumulation potential to form esters might impair signaling of phytanic acid followed by replacement of through hedgehog proteins and thus explain essential fatty acid with phytanic acid in the the dysplasias observed in CHILD syndrome. lipid moieties of various tissues. (5) Cathepsin C (9) LEKTI (lymphoepithelial Kazal-type- Papillon-Lefèvre syndrome is caused by the related inhibitor) mutation of the cathepsin C gene.5) Cathepsin C Netherton syndrome is caused by the muta- is a cysteine protease of the papain family and tion of the SPINK5 (serine protease inhibitor, is a dipeptidyl aminopeptidase capable of Kazal-type 5) gene, which codes LEKTI, a removing dipeptides from amino terminus of serine protease inhibitor.9) LEKTI is involved proteins. The Cathepsin C knockout mice show in T-cell differentiation in thymic epithelium insufficiency in the cytotoxic activity of CTL as well as anti-inflammatory and bactericidal cells and NK cells through activation impair- activities in mucosal epithelium. Defective ment of serine proteases called granzymes A LEKTI expression may cause unbalanced Th2 and B. In this disease, the immune response to immune response with markedly elevated IgE infections becomes abnormal via the same levels, increased susceptibility to infection and mechanism seen in the knockout mice and impaired desquamation of cornified cells. characteristically induces severe periodontitis. (6) Steroid sulfatase (STS) 2. Adhesion Molecules X-linked ichthyosis vulgaris is caused by the (1) Desmosome components mutation of the STS gene.6) STS is an enzyme Striate palmoplantar keratoderma, Naxos hydrolyzing the sulfate group at the sterol ring disease, and skin fragility syndrome are caused 3␤ position in steroid hormones and choles- by mutations of the desmoplakin gene or the terols. In this disease, the degradation of cho- desmoglein 1 gene, the plakoglobin gene, and 510 JMAJ, November 2004—Vol. 47, No. 11 THE MOLECULAR BASIS OF KERATINIZING DISORDERS the plakophilin gene, respectively.10–13) Desmo- associated with normal loricrin, and the forma- somes are intracellular adhesion apparatuses tion of the cornified cell envelope is impaired. occurring in epithelial cells and myocardial cells. The protein component of a desmosome 4. Cytoskeletal Proteins (Table 1) is composed of a group of transmembrane glyco- (1) Keratins proteins and a group of attachment plaque Various diseases collectively called keratin proteins binding to them on the cytoplasm side. diseases are caused by the mutation of various Desmoglein 1 belongs to the former group, and keratin genes.20) Keratins are an extremely desmoplakin, plakoglobin, and plakophylin diversified group of proteins that play an belong to the latter. Mutations in these desmo- important role in cell shape maintenance. In some components are considered to cause keratin diseases, the ability of keratins to main- abnormalities in cell adhesion, but little is tain cell shape is weakened, and cells are easily known about their relation to palmoplantar destroyed by even slight external force. keratosis, the common clinical manifestation of the above-mentioned
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