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).
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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
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,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
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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 diseases. 5. Others (2) Connexins (1) Dyskerin and telomerase RNA Erythrokeratoderma variabilis, Clouston syn- X-linked recessive dyskeratosis congenita drome, Vohwinkel’s syndrome with deafness and autosomal dominant dyskeratosis con- and KID (keratitis-ichthyosis-deafness) syn- genita are caused by mutations of the dyskerin drome are caused by mutations of the connexin gene and telomerase RNA gene, respectively.21,22) 31 gene, the connexin 30 gene and the connexin These components are suspected to play a role 26 gene, respectively.14–17) in the activity adjustment of telomerase, which Connexins are the main protein components governs the life span of cells. However, their of the gap junction. Six connexin molecules functional significance in these diseases is assembled in a ring form a doughnut-shaped unknown. structure. The tunnel at the center of this struc- (2) SLURP-1 (secreted Ly6/uPAR-related ture opens and closes to adjust the transporta- protein 1) tion of small molecules between adjacent cells, Mal de Meleda type of palmoplantar which play an important role in intercellular keratosis is caused by the mutation of the interaction. Mutant connexins are likely to be SLURP-1 gene.23) SLURP-1 belongs to the incapable not only of forming the normal gap leukocyte antigen-6 (Ly6)/urokinase-type plas- junction but also of playing a crucial role in minogen activator (uPAR) protein family, and epithelial homeostasis and differentiation. the structure of SLURP-1 suggests its relation- ship with snake and frog toxins. SLURP-1 3. Cornified Cell Envelope Proteins receptors are assumed to play an important (1) Loricrin role in signal transduction, cell growth, cell Both Vohwinkel syndrome with ichthyosis adhesion, etc., but their functional significance and progressive erythrokeratodermia are in this disease is unknown. caused by the mutation of the loricrin gene.18, 19) Loricrin deposits on the 15-nm-thick layer of 6. Diseases Being Studied for Identification the cytoplasmic surface of the cell periphery of Pathogenic Genes (cornified cell envelope). Frameshift mutations The genes for harlequin fetus and pal- in the loricrin gene produce amino acid moplantar keratoderma Howel-Evans map sequences that contain motifs resembling to chromosomes 18q21.3 and 17q25, re- nuclear localization signals. As a result, the spectively.24,25) mutant loricrin moves into the nucleus being
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Conclusion Nat Genet 2000; 25: 141–142. 10) Rickman, L., Simrak, D., Stevens, H.P. et al.: These findings of genes responsible for N-terminal deletion in a desmosomal cadherin keratinizing disorders are expected to provide causes the autosomal dominant skin disease striate palmoplantar keratoderma. Hum Mol valuable information in the elucidation of Genet 1999; 8: 971–976. pathogenic mechanisms and the search for new 11) Armstrong, D.K., McKenna, K.E., Purkis, P.E. treatment modalities. et al.: Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar REFERENCES keratoderma. Hum Mol Genet 1999; 8: 143– 148. 1) Jobard, F., Lefevre, C., Karaduman, A. et al.: 12) McKoy, G., Protonotarios, N., Crosby, A. et al.: Lipoxygenase-3 (ALOXE3) and 12 (R)- Identification of a deletion in plakoglobin in lipoxygenase (ALOX12B) are mutated in arrhythmogenic right ventricular cardiomyo- non-bullous congenital ichthyosiform eryth- pathy with palmoplantar keratoderma and roderma (NCIE) linked to chromosome woolly hair (Naxos disease). Lancet 2000; 355: 17p13.1. Hum Mol Genet 2002; 11: 107–113. 2119–2124. 2) Huber, M., Rettler, I., Bernasconi, K. et al.: 13) McGrath, J.A., McMillan, J.R., Shemanko, Mutations of keratinocyte transglutaminase in C.S. et al.: Mutations in the plakophilin 1 gene lamellar ichthyosis. Science 1995; 267: 525– result in ectodermal dysplasia/skin fragility 528. syndrome. Nat Genet 1997; 17: 240–244. 3) Sakuntabhai, A., Ruiz-Perez, V., Carter, S. 14) Richard, G., Smith, L.E., Bailey, R.A. et al.: et al.: Mutations in ATP2A2, encoding a Ca Mutations in the human connexin gene GJB3 pump, cause Darier disease. Nat Genet cause erythrokeratodermia variabilis. Nat (ם2) 1999; 21: 271–277. Genet 1998; 20: 366–369. 4) Konig, A., Happle, R., Bornholdt, D. et al.: 15) Maestrini, E., Korge, B.P., Ocana-Sierra, I. Mutations in the NSDHL gene, encoding a et al.: A missense mutation in connexin26, 3-beta-hydroxysteroid dehydrogenase, cause D66H, causes mutilating kerato-derma with CHILD syndrome. Am J Med Genet 2000; 90: sensorineural deafness (Vohwinkel’s syn- 339–346. drome) in three unrelated families. Hum Mol 5) Toomes, C., James, J., Wood, A.J. et al.: Loss- Genet 1999; 8: 1237–1243. of-function mutations in the cathepsin C gene 16) Richard, G., Rouan, F., Willoughby, C.E. et al.: result in periodontal disease and palmo- Missense mutations in GJB2 encoding plantar keratosis. Nat Genet 1999; 23: 421–424. connexin-26 cause the ectodermal dysplasia 6) Bonifas, J.M., Morley, B.J., Oakey, R.E. et al.: keratitis-ichthyosis-deafness syndrome. Am J Cloning of a cDNA for steroid sulfatase: Hum Genet 2002; 70: 1341–1348. frequent occurrence of gene deletions in 17) Lamartine, J., Munhoz Essenfelder, G., Kibar, patients with recessive X chromosome-linked Z. et al.: Mutations in GJB6 cause hidrotic ichthyosis. Proc Natl Acad Sci USA 1987; 84: ectodermal dysplasia. Nat Genet 2000; 26: 9248–9251. 142–144. 7) De Laurenzi, V., Rogers, G.R., Hamrock, D.J. 18) Maestrini, E., Monaco, A.P., McGrath, J.A. et et al.: Sjögren-Larsson syndrome is caused by al.: A molecular defect in loricrin, the major mutations in the fatty aldehyde dehydro- component of the cornified cell envelope, genase gene. Nat Genet 1996; 12: 52–57. underlies Vohwinkel’s syndrome. Nat Genet 8) Jansen, G.A., Ofman, R., Ferdinandusse, S. 1996; 13: 70–77. et al.: Refsum disease is caused by mutations 19) Ishida-Yamamoto, A., McGrath, J.A., Lam, H. in the phytanoyl-CoA hydroxylase gene. Nat et al.: The molecular pathology of progressive Genet 1997; 17: 190–193. symmetric erythrokeratoderma: a frameshift 9) Chavanas, S., Bodemer, C., Rochat, A. et al.: mutation in the loricrin gene and perturba- Mutations in SPINK 5, encoding a serine pro- tions in the cornified cell envelope. Am J Hum tease inhibitor, cause Netherton syndrome. Genet 1997; 61: 581–589.
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20) Yoneda, K., Takahira, Y., Idemitsu, T. et al.: Mutations in the gene encoding SLURP-1 in Keratin diseases. Pharma Medica 1999; 17: 83– Mal de Meleda. Hum Mol Genet 2001; 10: 87. 875–880. 21) Heiss, N.S., Knight, S.W., Vulliamy, T.J. et al.: 24) Stewart, H., Smith, P.T., Gaunt, L. et al.: De X-linked dyskeratosis congenita is caused by novo deletion of chromosome 18q in a baby mutations in a highly conserved gene with with harlequin ichthyosis. Am J Med Genet putative nucleolar functions. Nat Genet 1998; 2001; 102: 342–345. 19: 32–38. 25) Risk, J.M., Evans, K.E., Jones, J. et al.: Charac- 22) Vulliamy, T., Marrone, A., Goldman, F. et al.: terization of a 500kb region on 17q25 and the The RNA component of telomerase is exclusion of candidate genes as the familial mutated in autosomal dominant dyskeratosis Tylosis Oesophageal Cancer (TOC) locus. congenita. Nature 2001; 413: 432–435. Oncogene 2002; 21: 6395–6402. 23) Fischer, J., Bouadjar, B., Heilig, R. et al.:
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