Acral Peeling Skin Syndrome with TGM5 Gene Mutations May Resemble Epidermolysis Bullosa Simplex in Young Individuals
2010; Elsevier BV; Volume: 130; Issue: 6 Linguagem: Inglês
10.1038/jid.2010.23
ISSN1523-1747
AutoresDimitra Kiritsi, Ioana Cosgarea, Claus-Werner Franzke, Hauke Schumann, Vinzenz Oji, Jürgen Kohlhase, Leena Bruckner‐Tuderman, Cristina Has,
Tópico(s)Genetic and rare skin diseases.
Resumoacral peeling skin syndrome epidermolysis bullosa simplex transglutaminase TO THE EDITOR The acral peeling skin syndrome (APSS) is a rare autosomal recessive condition characterized by superficial painless peeling of the skin predominantly on the dorsal aspects of hands and feet (Shwayder et al., 1997Shwayder T. Conn S. Lowe L. Acral peeling skin syndrome.Arch Dermatol. 1997; 133: 535-536Crossref PubMed Scopus (28) Google Scholar; Cassidy et al., 2005Cassidy A.J. van Steensel M.A. Steijlen P.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). The condition is usually aggravated by heat, humidity, and exposure to water. Microscopically, the cleavage level is located in the upper epidermis, between the stratum granulosum and the stratum corneum (Garcia et al., 2005Garcia E.G. Carreno R.G. Martinez Gonzalez M.A. et al.Acral peeling skin syndrome: report of two cases.Ultrastruct Pathol. 2005; 29: 65-70Crossref PubMed Scopus (7) Google Scholar). Only 15 patients with APSS have been reported since 1997 (Shwayder et al., 1997Shwayder T. Conn S. Lowe L. Acral peeling skin syndrome.Arch Dermatol. 1997; 133: 535-536Crossref PubMed Scopus (28) Google Scholar; Brusasco et al., 1998Brusasco A. Veraldi S. Tadini G. et al.Localized peeling skin syndrome: case report with ultrastructural study.Br J Dermatol. 1998; 139: 492-495Crossref PubMed Scopus (22) Google Scholar; Hashimoto et al., 2000Hashimoto K. Hamzavi I. Tanaka K. et al.Acral peeling skin syndrome.J Am Acad Dermatol. 2000; 43: 1112-1119Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar; Cassidy et al., 2005Cassidy A.J. van Steensel M.A. Steijlen P.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar; Garcia et al., 2005Garcia E.G. Carreno R.G. Martinez Gonzalez M.A. et al.Acral peeling skin syndrome: report of two cases.Ultrastruct Pathol. 2005; 29: 65-70Crossref PubMed Scopus (7) Google Scholar; Kharfi et al., 2009Kharfi M. El Fekih N. Ammar D. et al.A missense mutation in TGM5 causes acral peeling skin syndrome in a Tunisian family.J Invest Dermatol. 2009; 129: 2512-2515Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar; Oumakhir et al., 2009Oumakhir S. Hjira N. Albouzidi A. et al.[Plantar acral peeling skin syndrome].Ann Dermatol Venereol. 2009; 136: 391-392Crossref PubMed Scopus (4) Google Scholar; Wakade et al., 2009Wakade O. Adams B. Shwayder T. Acral peeling skin syndrome: a case of two brothers.Pediatr Dermatol. 2009; 26: 328-330Crossref PubMed Scopus (9) Google Scholar) (Table 1). In several of them, in addition to superficial peeling, acral blisters were also described (Wakade et al., 2009Wakade O. Adams B. Shwayder T. Acral peeling skin syndrome: a case of two brothers.Pediatr Dermatol. 2009; 26: 328-330Crossref PubMed Scopus (9) Google Scholar). The genetic basis of the disease was determined in only three families, in whom two different missense mutations in the TGM5 gene encoding transglutaminase 5 (TGase 5) were disclosed (Table 1) (Cassidy et al., 2005Cassidy A.J. van Steensel M.A. Steijlen P.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar; Kharfi et al., 2009Kharfi M. El Fekih N. Ammar D. et al.A missense mutation in TGM5 causes acral peeling skin syndrome in a Tunisian family.J Invest Dermatol. 2009; 129: 2512-2515Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). It remains unclear whether the other patients have mutations in the same gene, or whether APSS is clinically and genetically heterogeneous (Cassidy et al., 2005Cassidy A.J. van Steensel M.A. Steijlen P.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar).Table 1Patients in this study and review of the literaturePatientOriginAge at examination (years)Age at onsetSymptomsLocalizationAggravating factorsTGM5 mutations (protein level)Reference1Sweden22 moBlisters, peeling, erythemaVolar and dorsal aspects of hands and feetHeat, sweatingp.[Gly113Cys]+[Trp255Arg]This study2Germany6BirthBlisters, peelingVolar and dorsal aspects of hands and feetHeat and mechanical traumap.[Gly113Cys]+[Gly113Cys]This study3Finland13 moBlisters, peelingVolar and dorsal aspects of hands and feetNAp.[Gly113Cys]+[Gly113Cys]This study4Germany47Shortly after birthBlisters, peeling, erythema, and itching when healingVolar and dorsal aspects of hands and feet, elbowsHeat, sweat, long baths, and traumap.[Gly113Cys]+[Gly113Cys]This study5Germany121 yBlistersFeetMechanical traumap.[Gly113Cys]+[Gly113Cys]This study6Germany12NANANANAp.[Gly113Cys]+[Gly113Cys]This study7Germany1BirthBlisters, peelingHands and feetNAp.[Gly113Cys]+[Gly113Cys]This study8Germany2Shortly after birthBlisters, peeling, erythemaPalms and solesHeatp.[Gly113Cys]+[Gly113Cys]This study9Germany4BirthBlisters, peeling, erythemaVolar and dorsal aspects of hands and feetHeatp.[Gly113Cys]+[Gly113Cys]This study101The patients 10–11, 12–16, and 18–19 are siblings.Tunisia53 yPainless superficial skin peelingVolar and dorsal aspects of hands and feetHeat, humidity, frictionp.[Lys445Asn]+[Lys445Asn]Kharfi et al., 2009Kharfi M. El Fekih N. Ammar D. et al.A missense mutation in TGM5 causes acral peeling skin syndrome in a Tunisian family.J Invest Dermatol. 2009; 129: 2512-2515Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar111The patients 10–11, 12–16, and 18–19 are siblings.Tunisia3NAPainless superficial skin peelingVolar and dorsal aspects of hands and feetHeat, humidity, frictionp.[Lys445Asn]+[Lys445Asn]Kharfi et al., 2009Kharfi M. El Fekih N. Ammar D. et al.A missense mutation in TGM5 causes acral peeling skin syndrome in a Tunisian family.J Invest Dermatol. 2009; 129: 2512-2515Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar12–161The patients 10–11, 12–16, and 18–19 are siblings.The NetherlandsNANAPainless superficial skin peeling, erythemaDorsal aspects of hands and feetHeat and humidityp.[Gly113Cys]+[Gly113Cys]Cassidy et al., 2005Cassidy A.J. van Steensel M.A. Steijlen P.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar17ScotlandNANAPainless superficial skin peeling, erythemaDorsal aspects of hands and feetHeat and humidityp.Gly113Cys+[Gly113Cys]Cassidy et al., 2005Cassidy A.J. van Steensel M.A. Steijlen P.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar181The patients 10–11, 12–16, and 18–19 are siblings.Middle East155 yFlaccid blisters and shallow erosionsDorsal aspects of hands and feetHeat and humidityNAWakade et al., 2009Wakade O. Adams B. Shwayder T. Acral peeling skin syndrome: a case of two brothers.Pediatr Dermatol. 2009; 26: 328-330Crossref PubMed Scopus (9) Google Scholar191The patients 10–11, 12–16, and 18–19 are siblings.Middle East6NAFlaccid blisters and shallow erosionsDorsal aspects of hands and feetHeat and humidityNAWakade et al., 2009Wakade O. Adams B. Shwayder T. Acral peeling skin syndrome: a case of two brothers.Pediatr Dermatol. 2009; 26: 328-330Crossref PubMed Scopus (9) Google Scholar20Morocco1710 ySuperficial peeling, hyperpigmentationLateral aspects of feetSoaking in waterNAOumakhir et al., 2009Oumakhir S. Hjira N. Albouzidi A. et al.[Plantar acral peeling skin syndrome].Ann Dermatol Venereol. 2009; 136: 391-392Crossref PubMed Scopus (4) Google Scholar21Spain1411 yWrinkling and peelingPalms in the tips of the fingers, solesSoaking in waterNAGarcia et al., 2005Garcia E.G. Carreno R.G. Martinez Gonzalez M.A. et al.Acral peeling skin syndrome: report of two cases.Ultrastruct Pathol. 2005; 29: 65-70Crossref PubMed Scopus (7) Google Scholar22Spain20NAEdematous whitish papules and shedding of the skinHandsSoaking in waterNAGarcia et al., 2005Garcia E.G. Carreno R.G. Martinez Gonzalez M.A. et al.Acral peeling skin syndrome: report of two cases.Ultrastruct Pathol. 2005; 29: 65-70Crossref PubMed Scopus (7) Google Scholar23The United States34“Lifelong”Superficial skin peeling, erythema, burningDorsal and volar aspects of hands and feet, rarely on elbows, forearms, shinsHeat, humidity, sweating, mechanical traumaNAHashimoto et al., 2000Hashimoto K. Hamzavi I. Tanaka K. et al.Acral peeling skin syndrome.J Am Acad Dermatol. 2000; 43: 1112-1119Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar; Shwayder et al., 1997Shwayder T. Conn S. Lowe L. Acral peeling skin syndrome.Arch Dermatol. 1997; 133: 535-536Crossref PubMed Scopus (28) Google Scholar24Italy266 yErythematous and thin-scaling patchesPalms, dorsal side of the fingersNo aggravationNABrusasco et al., 1998Brusasco A. Veraldi S. Tadini G. et al.Localized peeling skin syndrome: case report with ultrastructural study.Br J Dermatol. 1998; 139: 492-495Crossref PubMed Scopus (22) Google ScholarAbbreviations: mo, months; NA, not available; y, years.1 The patients 10–11, 12–16, and 18–19 are siblings. Open table in a new tab Abbreviations: mo, months; NA, not available; y, years. In this study, we investigated nine unrelated patients, eight children and one adult, clinically suspected to have epidermolysis bullosa simplex (EBS) because of acral skin blistering. The patients and/or diagnostic samples were referred to the Epidermolysis bullosa Center of the University Medical Center Freiburg (Volz et al., 2007Volz A. Has C. Schumann H. et al.Network epidermolysis bullosa: molecular pathomechanisms and novel therapeutic approaches.J Dtsch Dermatol Ges. 2007; 5: 274-279Crossref PubMed Scopus (7) Google Scholar) for molecular diagnostics of EBS. EDTA-blood and skin samples were obtained after informed consent of the patients and, if available, of family members. EDTA-blood samples of 50 clinically unaffected Central European individuals were used as controls. The study was conducted according to the Declaration of Helsinki Principles. Immunofluorescence staining of skin cryosections was performed using a panel of antibodies to components of the epidermal basement membrane zone (Kern et al., 2006Kern J.S. Kohlhase J. Bruckner-Tuderman L. et al.Expanding the COL7A1 mutation database: novel and recurrent mutations and unusual genotype-phenotype constellations in 41 patients with dystrophic epidermolysis bullosa.J Invest Dermatol. 2006; 126: 1006-1012Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar), as well as antibodies to loricrin (Abcam, Cambridge, UK), filaggrin (clone 15C10; Novocastra, Newcastle, UK), involucrin (clone SY5; Sigma, Taufkirchen, Germany), cytokeratin 10 (clone DE-K10; Dako, Glostrup, Denmark), TGase 1 (clone B.C1; Biomedical Technologies, Madrid Spain), TGase 3 (Jackson Immunoresearch Laboratories, West Grove, PA), and TGase 5 (Novus Biologicals, Littleton, CO). Genomic DNA was extracted from EDTA-blood using the QiAmp DNA mini kit (Qiagen, Hilden, Germany). Amplification of all KRT5 (NC_000012.11, National Center for Biotechnology Information (NCBI)), KRT14 (NC_000017.10, NCBI), and TGM5 (NC_000015.9, NCBI) exons and exon–intron boundaries, and sequencing were performed as described (Schuilenga-Hut et al., 2003Schuilenga-Hut P.H. Vlies P. Jonkman M.F. et al.Mutation analysis of the entire keratin 5 and 14 genes in patients with epidermolysis bullosa simplex and identification of novel mutations.Hum Mutat. 2003; 21: 447Crossref PubMed Scopus (40) Google Scholar; Wood et al., 2003Wood P. Baty D.U. Lane E.B. et al.Long-range polymerase chain reaction for specific full-length amplification of the human keratin 14 gene and novel keratin 14 mutations in epidermolysis bullosa simplex patients.J Invest Dermatol. 2003; 120: 495-497Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar; Cassidy et al., 2005Cassidy A.J. van Steensel M.A. Steijlen P.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Mutations were confirmed by resequencing. The mutation c.763T>C was verified in 100 control chromosomes by digestion with the restriction enzyme BsrBI according to the manufacturer's protocol (NEBioLabs, Ipswich, MA). Predictions regarding the consequences of the mutation and modeling were performed using the software Polyphen (http://coot.embl.de/PolyPhen/) and SWISS-MODEL (http://swissmodel.expasy.org/workspace/index.php?func=modelling) (Guex and Peitsch, 1997Guex N. Peitsch M.C. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling.Electrophoresis. 1997; 18: 2714-2723Crossref PubMed Scopus (9111) Google Scholar). The clinical phenotypes of the nine patients in this study are summarized in Table 1. It is noteworthy that eight of the nine patients are children of 12 years of age or younger, with only one adult in the cohort. Eight had had blisters at birth or since infancy (Figure 1a); for patient 6, no information was available. Healing occurred spontaneously, sometimes with residual erythema, burning sensation, or pruritus, but without scarring or atrophy. Aggravation was caused by sweating, heat, and humidity, or by mechanical trauma. In most cases, only the volar and dorsal aspects of hands and feet were affected, but in the 47-year-old patient 4, exfoliation also occurred on elbows and knees (Figure 1c). In older children and in the adult patient, peeling of the skin was the most prominent symptom, but blisters occurred occasionally. Interestingly, three of the patients reported having a parent (patients 5 and 9) or offspring (patient 4) with mild features of the disease. In the skin samples of the patients, there were no abnormalities of the basement membrane zone, and all markers stained positive. This result is compatible with the diagnosis of localized EBS, because in these patients fragility of the skin is not prominent. In our experience, in the biopsy samples sent for immunofluorescence mapping to the Epidermolysis bullosa Center Freiburg, tissue separation is observed only in about a third of the localized EBS cases. Furthermore, keratin staining is usually not altered. In some samples in the present cohort, a discrete split in the stratum corneum was present (Figure 2), suggesting the diagnosis of APSS, which was thereafter confirmed by mutation analysis. Mutations in the exons and intron/exon boundaries of the KRT5 and KRT14 genes were excluded in all patients. In patients 2–9, the TGM5 mutation c.337G>T, p.Gly113Cys was disclosed in a homozygous state. As reported before (Cassidy et al., 2005Cassidy A.J. van Steensel M.A. Steijlen P.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar), the mutation was associated with the single-nucleotide polymorphism p.Thr109Met, also in a homozygous state. The father of patient 5 and the parents of patient 7 were heterozygous carriers of the mutation and single-nucleotide polymorphism, respectively. Patient 1 was compound heterozygous for p.Gly113Cys and for the mutation c.763T>C, p.Trp255Arg (Figure 2e). To our knowledge, this mutation is previously unreported and was excluded among 100 control chromosomes by restriction digestion with BsrBI. Tryptophan 255 is conserved in all TGases in different species and lies within the core domain close to the catalytic active site of TGase 5 (see Supplementary Figure S1 online). Download .pdf (1.71 MB) Help with pdf files Supplementary Figure 1 The three-dimensional structure of the core domain of the wild-type and Trp255Arg-mutated TGase 5 was modeled using the closely related TGase 3 as a template (PDB ID, 1I9mA; chain ID, 4) (Grenard et al., 2001Grenard P. Bates M.K. Aeschlimann D. Evolution of transglutaminase genes: identification of a transglutaminase gene cluster on human chromosome 15q15. Structure of the gene encoding transglutaminase X and a novel gene family member, transglutaminase Z.J Biol Chem. 2001; 276: 33066-33078Crossref PubMed Scopus (168) Google Scholar). This model revealed proximity of amino-acid 255 to the catalytic site of the enzyme and the conformation changes induced by the amino-acid substitution (Supplementary Figure S1). Because the mutation substitutes the large nonpolar neutral tryptophan with the smaller, polar and positively charged arginine, we performed a prediction of electrostatic potentials using the Poisson–Boltzmann equation. This revealed significant differences in electrostatic potentials between wild-type (Trp255) and mutated (Arg255) core domains (Supplementary Figure S1). Significantly, the amino-acid stretch Ser492–Ser501, which has been recently described as an important cleavage region for proteolytic activation of TGase 5 (Pietroni et al., 2008Pietroni V. Di Giorgi S. Paradisi A. et al.Inactive and highly active, proteolytically processed transglutaminase-5 in epithelial cells.J Invest Dermatol. 2008; 128: 2760-2766Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar), was strongly affected by conformation and electrostatic changes. Therefore, we predict that the mutation has a considerable impact on TGase 5, inducing conformation and electrostatic changes. Compared to wild type, the mutated TGase 5 was restricted to a few cell layers. Similar to TGase 1 (Raghunath et al., 1998Raghunath M. Hennies H.C. Velten F. et al.A novel in situ method for the detection of deficient transglutaminase activity in the skin.Arch Dermatol Res. 1998; 290: 621-627Crossref PubMed Scopus (58) Google Scholar), missense mutations may alter activity but not enzyme expression. In APSS skin, TGase 1 staining was diffuse, but TGase 3 was not changed (Figure 2). Kinetic and in vitro experiments have indicated that TGase 5 is very efficient in cross-linking loricrin, involucrin, and small proline-rich proteins (Candi et al., 2001Candi E. Oddi S. Terrinoni A. et al.Transglutaminase 5 cross-links loricrin, involucrin, and small proline-rich proteins in vitro.J Biol Chem. 2001; 276: 35014-35023Crossref PubMed Scopus (89) Google Scholar). Therefore, we investigated the effect of TGase 5 mutations on the distribution of loricrin, involucrin, and filaggrin in the skin of five patients in vivo (1–5). Interestingly, all three proteins were distributed in a more diffuse manner in patients' skin samples compared to controls (Figure 2). However, the molecular mechanisms behind these findings remain to be elucidated. Taken together, we report that patients with clinically suspected EBS carried TGM5 mutations and in fact suffered from APSS. Such an initial assumption of epidermolysis bullosa has been reported in literature before (Hashimoto et al., 2000Hashimoto K. Hamzavi I. Tanaka K. et al.Acral peeling skin syndrome.J Am Acad Dermatol. 2000; 43: 1112-1119Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar) and is understandable for several reasons: first, in infants, APSS frequently manifests with blistering on palms and soles and is aggravated by mechanical factors and by a humid, warm environment. Second, in three families, a vertical transmission of the disease was considered because either parents or offspring were reported to have had skin blistering in childhood. Third, similar to that observed occasionally in localized EBS, no tissue separation was detected by light microscopic examination of skin biopsies. The superficial skin split visible in some skin sections was considered to be an artifact in cryosections. For these reasons, the diagnosis of APSS was missed. Moreover, the presumption that APSS affects only the dorsal regions of the hands and feet (Cassidy et al., 2005Cassidy A.J. van Steensel M.A. Steijlen P.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) might have confused some clinicians. On the basis of the above, we consider APSS to be an important differential diagnosis for EBS, which certainly accounts for a number of cases in which keratin mutations were not identified. Indeed, of 83 individuals referred to us with suspected EBS, 11% had TGM5 mutations and APSS. Importantly, the TGM5 mutation p.Gly113Cys was identified in nine unrelated patients, which suggests that it is a recurrent, possibly an ancestral, mutation in the European population (Cassidy et al., 2005Cassidy A.J. van Steensel M.A. Steijlen P.M. et al.A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.Am J Hum Genet. 2005; 77: 909-917Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). This finding has practical consequences for diagnostic testing in patients suspected to have EBS but no keratin mutations. In such cases, screening of the recurrent TGM5 mutation p.Gly113Cys is easy and rapid. Finally, molecular genetics will shed light on the different APSS phenotypes. On the basis of the knowledge on related skin diseases such as epidermolysis bullosa, genetic and phenotypic heterogeneity should be expected. We thank all patients who participated in this study and the physicians who sent us samples. The excellent technical support by Gabriele Grüninger, Vera Morand, and Kaethe Thoma is gratefully acknowledged. This work was supported by the Network Epidermolysis Bullosa grant from the Federal Ministry for Education and Research (BMBF) to LBT, the Excellence Initiative of the German Federal and State Governments and the Freiburg Institute for Advanced Studies, FRIAS, School of Life Sciences to LBT, and by the K Kriezis scholarship from the National and Kapodistrian University of Athens to DK. The study protocol was approved by the ethics committee of the University Medical Center Freiburg. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
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