(2014) provide mechanistic insight intothe response of melanocytes to oxida-tive stress and their role in the patho-genesis of vitiligo. This study opens thepossibility that the Nrf2–ARE pathwaycould be exploited as a preventive and/or therapeutic strategy to counter oxida-tive damage in melanocytes, as well asto dampen IL-2 production.

There are several limitations to thisstudy, specifically as it relates to mela-nocytes in vivo and the potential forclinical translation. First, the melano-cytes used in this study are immortalizedcell lines, which may exhibit alteredoxidative stress responses comparedwith primary melanocytes. Immunohis-tochemical evaluation of the levels/loca-lization of Nrf2 and/or antioxidantenzymes in normal and lesional skinwill be of considerable value. This willalso address the role of keratinocyteantioxidant responses in vitiligo patho-genesis, as keratinocytes are thought tobe ROS donors to melanocytes. Second,although H2O2 is a widely used andwidely accepted oxidative stress indu-cer, additional stressors may need tobe tested to confirm the role of theNrf2–ARE pathway. Third, although pro-vocative, the observations on the inverserelationship between serum HO-1 andIL-2 levels do not identify the source ofHO-1 (melanocyte intracellular vs. sys-temically derived) or the correlationsamong serum HO-1, IL-2 levels, andlesional T lymphocyte accumulation.These limitations notwithstanding, thisstudy by Jian et al. (2014) shines aspotlight on antioxdative mechanismsin vitiligo and highlights the need toexplore strategies to restore a balancedredox system, thereby protectingmelanocytes from destruction.

CONFLICT OF INTERESTThe authors state no conflict of interest.

ACKNOWLEDGMENTSThis research was supported in part by the grantR21AR062734 to VS from the National Institutes ofArthritis and Musculoskeletal and Skin Diseases.This study was supported by the National Institutesof Health.

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Itoh K, Wahabayashi N, Katoh Y et al. (1999)Keap1 represses nuclear activation of antiox-idant responsive elements by Nrf2 through

binding to the amino-terminal Neh2 domain.Genes Dev 13:76–86

Jian Zhe, Li Kai, Song Pu et al. (2014) Impairedactivation of Nrf2-ARE signaling pathwayundermines H2O2-induced oxidative stressresponse: a possible mechanism for melano-cyte degeneration in vitiligo. J InvestDermatol 134:2221–30

Kensler TW, Wakabayashi N, Biswal S (2007) Cellsurvival responses to environmental stressesvia the Keap1-Nrf2-ARE pathway. Annu RevPharmacol Toxicol 47:89–116

Marrot L, Jones C, Perez P et al. (2008) Thesignificance of Nrf2 pathway in (photo)-oxi-dative stress response in melanocytes andkeratinocytes of the human epidermis. Pig-ment Cell Melanoma Res 21:79–88

Pae HO, Oh GS, Choi BM et al. (2004) Carbonmonoxide produced by heme oxygenase-1suppresses T cell proliferation via inhibitionof IL-2 production. J Immunol 172:4744–51

Taieb A (2000) Intrinsic and extrinsic pathome-chanisms in vitiligo. Pigment Cell Res 13(Suppl 8):41–7

See related article on pg 2269

Nagashima-Type PalmoplantarKeratosis: A Common Asian TypeCaused by SERPINB7 ProteaseInhibitor DeficiencyAkiharu Kubo1

Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive diffusenon-epidermolytic palmoplantar keratosis caused by mutations in SERPINB7, amember of the serine protease inhibitor superfamily. Genetic studies suggest thatNPPK is the most common palmoplantar keratosis in Japan, and probably Asia,but one that is extremely rare in Western countries. In this issue, Yin et al. report afounder effect of a SERPINB7 mutation in Chinese populations.

Journal of Investigative Dermatology (2014) 134, 2076–2079. doi:10.1038/jid.2014.156

Establishment of a new entity of

palmoplantar keratosis

Nagashima-type palmoplantar keratosis(NPPK; MIM 615598) is a comparativelynew entity of palmoplantar keratosis(PPK). Masaji Nagashima first describedthis disease briefly in 1977 as a form ofPPK showing a similar distribution oflesions to, but a considerably milderdisease phenotype than, Mal de Meleda(MIM 248300) (Nagashima, 1977). Inde-pendently, Mitsuhashi and Hashimato(1989) observed a Japanese patient whohad reddish diffuse mild PPK extendingto the dorsal surfaces of the hands andfeet. Together with UW Schnyder, aSwiss specialist in genetic skin diseaseswho investigated Mal de Meleda inthe Adriatic island of Mljet (Meleda)(Schnyder, 1969), they concluded that

the patient’s phenotype was far milderthan that of Mal de Meleda. Ultimately,they reported siblings with the samedistinct disease phenotype and con-cluded that the disease was a novelautosomal recessive PPK, designating itas ‘‘keratosis palmoplantaris Nagashima’’(Mitsuhashi and Hashimato, 1989).Because of its probable very lowprevalence in Western countries, thisdisease entity has long been recognizedonly in Japan. In 2008, Kabashima et al.(2008) introduced NPPK to internationalsocieties with a detailed description ofthe disease phenotype, and they pro-posed NPPK as a distinct clinical entitybecause of the lack of mutations in theexonic region of SLURP1, the causa-tive gene of Mal de Meleda. In 2013,Kubo et al. (2013) finally identified the

1Department of Dermatology, Keio University School of Medicine, Tokyo, Japan

Correspondence: Akiharu Kubo, Department of Dermatology, Keio University School of Medicine,Shinanomachi 35, Tokyo, Shinjuku 160-8582, Japan. E-mail: akiharu@a5.keio.jp

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causative gene mutations as residing inSERPINB7, a member of the serineprotease inhibitor superfamily, in 13unrelated Japanese NPPK patients viaexome sequencing, and they establishedNPPK as a novel disease entity. As themajor causative mutation, c.796C4T(p.R266*) in SERPINB7, was found in8/286 Japanese and Chinese individualsin the 1000 Genomes Database (http://browser.1000genomes.org), the mutationhas been proposed to be distributedwidely among Asian populations (Kuboet al., 2013). In this issue, Yin et al. nowcharacterize NPPK patients from China,and they confirm the founder effect ofthe c.796C4T mutation in SERPINB7among a second Asian population.

NPPK is characterized clinically bywell-demarcated reddish, diffuse, andmild palmoplantar non-epidermolytichyperkeratosis that extends to the dorsalsurfaces of the hands and feet, innerwrists, ankles, and the Achilles tendonarea (Figure 1). High frequencies ofhyperhidrosis on palms and soles and

tinea infection have been noted. Theaffected areas and clinical manifes-tations are non-progressive, which isthe major clinical difference fromMal de Meleda. The palms and solesof NPPK patients show a whitish spongyappearance within 10 minutes of waterexposure specifically in the reddishhyperkeratotic area (Figure 1c and d;Kubo et al., 2013; Yin et al., 2014).

A widespread founder mutation in

SERPINB7 causes NPPK as a common

PPK in Asian populations

Whitish changes in the palms andsoles after water exposure have alsobeen reported in autosomal dominantBothnian-type PPK (MIM 600231)caused by AQP5 mutations. Yin et al.investigated the seven Chinese PPKpatients with reddish mild hyperkerato-sis showing whitish spongy changesafter water exposure and showed thatall seven patients had bi-allelic muta-tions in SERPINB7, but not in AQP5.Taken together with the fact that 9 cau-

sative mutations in SERPINB7 but nocausative mutations in AQP5 werefound in 286 Japanese and Chinese indi-viduals in the 1000 Genomes Database,NPPK is suggested to be more commonthan Bothnian-type PPK in Japaneseand Chinese populations. As othertypes of PPK have considerably lowerprevalences, NPPK is likely the mostcommon type of PPK in Asian popu-lations.

Among SERPINB7 mutations in NPPK,10 of the 14 alleles of Chinese patientsand 19 of the 26 alleles of Japanesepatients were c.796C4T (Kubo et al.,2013; Yin et al., 2014). Haplotypeanalysis in Chinese patients suggestedthat c.796C4T is a founder mutation,instead of a mutation hotspot (Yin et al.,2014). The c.796C4T mutation was notfound in 806 individuals of non-Asianorigin in the 1000 Genomes Databaseor 12,517 alleles of European-Americanand African-American origin in theNHBLI Exome Variant Server (http://evs.gs.washington.edu/EVS/). These resultsindicates that the c.796C4T mutationhas spread widely among Asian popu-lations due to its founder effect,which explains why NPPK is socommon in Japan and probably inChina but has not been reported inWestern countries.

NPPK is a new serpin-related congenital

disease

SERPINB7 is a member of the SERineProtease INhibitor (Serpin) superfamily.Human serpins have been divided intonine clades (A-I). In general, proteaseinhibitors are resistant to protease-dependent degradation. If they are sen-sitive to proteases, it is not possible forthem to function as protease inhibitors.As stable as they are, some serpins havelost their protease inhibitory activitiesduring the course of evolution, becom-ing storage proteins. For example, oval-bumin is a homolog of the clade Bserpins, one that has lost its proteaseinhibitory activity. Therefore, clade Bserpins, including SERPINB7, are alter-natively known as ov-serpins.

There are two major mechanismsby which mutations in SERPINs causecongenital diseases. One is that lossof protease inhibitory activity results inuncontrolled protease activity and tissue

Figure 1. Clinical appearance of Nagashima-type palmoplantar keratosis. (a, b) ‘‘Transgrediens’’ of the

reddish mild hyperkeratosis on the dorsal surfaces of the feet and Achilles tendon area. (c, d) Whitish

spongy changes on the hands after 10 minutes of water exposure. (d) ‘‘Transgrediens’’ on the dorsal

surfaces of the hands.

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destruction. For example, deficiency ofSERPINF2 (alpha2-antiplasmin) causes ableeding disorder through uncontrolledplasmin activity and fibrinolysis (MIM262850). The second mechanism is thatformation of protease-resistant hyper-stable misfolded polymers or aggregatesof mutant serpins in serpin-synthesizingcells results in cell death and tissuedamage. Such diseases are called ‘‘ser-pinopathies.’’ For example, familialencephalopathy with neuroserpin inclu-sion bodies (MIM 604218) is a serpino-pathy of SERPINI1 (neuroserpin) inwhich neurodegeneration is causedby aberrant protein processing andtissue deposition of SERPINI1 mutants.In some diseases, both mechanismsare involved. Deficiency of SERPINA1(alpha1-antitrypsin) causes not onlyemphysema through proteolytic lungdamage due to neutrophil elastaseinduced by the decreased plasmaalpha1-antitrypsin level but also liverdamage and cirrhosis through forma-tion of hyperstable polymers of mutantalpha1-antitrypsin in the endoplasmicreticulum of liver cells (MIM 613490).

Probable loss of protease inhibitory

activity in SERPINB7 causes NPPK

Clade B serpins are intracellular serpinsthat possibly protect cells from exogen-ous and endogenous protease-mediatedinjury. SERPINB7 is expressed in thecytoplasm of stratum granulosumcells (Kubo et al., 2013). Although thetarget protease of SERPINB7 has notbeen identified, the protease inhibitoryactivity of SERPINB7 has been demon-strated by plasmin inhibition assay(Miyata et al., 2002). In NPPK, inclu-sion bodies or protein aggregates havenot been detected in the stratum granu-losum or stratum corneum, suggestingthat formation of mutated SERPINB7polymers does not occur in NPPKpatient skin. The reactive site loop indis-pensable for protease inhibitory activityis located at the C-terminus of SERPINB7and is absent in all of the identifiedmutants due to the introduction of pre-mature stop codons by nonsense, frame-shift, or splice-site mutations. Therefore,NPPK is presumably caused by the lossof protease inhibitory activity of, and notpolymer formation by, SERPINB7 in theepidermis.

A widespread foundermutation in SERPINB7causes NPPK as acommon PPK in Asianpopulations.

One of the characteristics of NPPK isthe distribution of the reddish hyper-keratosis, extending to the dorsal sur-faces of the hands and feet and Achillestendon area, which is known as ‘‘trans-grediens.’’ SERPINB7 is expressed notonly in palmoplantar skin but also in theskin of other body areas (Kubo et al.,2013). In several types of diffuse PPKwith or without associated features,while the causative gene productshave a widespread expression pattern,the disease is mostly restricted to thepalmoplantar area. Although the mecha-nism of this discrepancy is as yetunknown, such PPKs include Vohwinkelsyndrome (MIM 604117) caused byloricrin (LOR) mutations, PPK with deaf-ness (MIM 148350) caused by connexin26 (GJB2) mutations, and Mal de Meledacaused by SLURP1 mutations. Interest-ingly, these PPKs, as well as NPPK, show‘‘transgrediens’’ to the dorsal surfaces ofthe hands and feet. By contrast, PPKscaused by mutations of palmoplantar-area-specific genes such as KRT9(Vorner-type PPK (MIM 144200)) do notshow such ‘‘transgrediens.’’ Future studieswill reveal the factor that restricts theaffected area to the palms and solesmainly in NPPK, despite widespreadexpression of SERPINB7.

Is NPPK caused by imbalance between

proteases and protease inhibitors in skin

homeostasis?

Various proteases, including serine pro-teases, exist in the stratum granulosumand the stratum corneum: intracellularproteases, such as caspase 14, asparticpeptidase retroviral-like 1/SASPase,and bleomycin hydrolase responsiblefor filaggrin degradation; endolysosomalproteases, such as cystatins and cathe-psins; secreted proteases, such askallikreins and kallikrein-related pepti-dases responsible for desquamation;and transmembrane proteases, such asmatriptase/suppression of tumorigenicity14 (ST14) and prostatin/protease serine

S1 family member 8 (PRSS8) (Meyer-Hoffert, 2009; Ovaere et al., 2009).Additionally, the epidermis is attackedby various exogenous proteases, origina-ting from bacteria, fungi, viruses, pollen,and house dust mites, and endogenousproteases such as neutrophil elastase andmast cell chymase, originating from infil-trating cells. It is likely that the epidermisexpresses various protease inhibitors,such as LEKTI, LEKTI-2, secretoryleukocyte protease inhibitor, elafin/skin-derived protease inhibitor, serpins, andcystatins, to control the activity of theseproteases (Meyer-Hoffert, 2009). LEKTIdeficiency results in Netherton syn-drome (MIM 256500), in which overacti-vation of kallikreins and a Par2 signalingcascade have been demonstrated(Descargues et al., 2005b; Deraisonet al., 2007; Briot et al., 2009). Studiesof transgenic mice with induced over-expression of Prss8 or Par2 reported skininflammatory responses and ichthyosis(Frateschi et al., 2011). Knockoutmouse studies targeting proteases (Prss8,matriptase/St14, and caspase 14) orprotease inhibitors (Spink5/LEKTI andcystatin E/M) showed skin barrier defi-ciencies and/or inflammation (List et al.,2002; Zeeuwen et al., 2002; Leyvrazet al., 2005; Descargues et al., 2005a;Denecker et al., 2007). Thus, appropriatecontrol of the activity of these proteasesis likely important in maintaining skinhomeostasis. However, their regulatorymechanisms remain mostly unknown.The discovery of loss-of-function muta-tions in SERPINB7 in NPPK shouldprovide insight into the functions andregulatory mechanisms of proteases andprotease inhibitors in the epidermis.

CONFLICT OF INTERESTThe author states no conflict of interest.

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Briot A, Deraison C, Lacroix M et al. (2009)Kallikrein 5 induces atopic dermatitis-likelesions through PAR2-mediated thymic stro-mal lymphopoietin expression in Nethertonsyndrome. J Exp Med 206:1135–47

Denecker G, Hoste E, Gilbert B et al. (2007) Caspase-14 protects against epidermal UVB photodam-age and water loss. Nat Cell Biol 9:666–74

Deraison C, Bonnart C, Lopez F et al. (2007) LEKTIfragments specifically inhibit KLK5, KLK7, andKLK14 and control desquamation through apH-dependent interaction. Mol Biol Cell18:3607–19

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Descargues P, Deraison C, Bonnart C et al. (2005a)Spink5-deficient mice mimic Netherton syn-drome through degradation of desmoglein 1by epidermal protease hyperactivity. NatGenet 37:56–65

Descargues P, Deraison C, Bonnart C et al. (2005b)Spink5-deficient mice mimic Netherton syn-drome through degradation of desmoglein 1by epidermal protease hyperactivity. NatGenet 37:56–65

Frateschi S, Camerer E, Crisante G et al. (2011) PAR2absence completely rescues inflammationand ichthyosis caused by altered CAP1/Prss8expression in mouse skin. Nat Commun 2:161

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cause Nagashima-type palmoplantar kerato-sis. Am J Hum Genet 93:945–56

Leyvraz C, Charles R-P, Rubera I et al. (2005)The epidermal barrier function is dependenton the serine protease CAP1/Prss8. J Cell Biol170:487–96

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Meyer-Hoffert U (2009) Reddish, scaly, and itchy:how proteases and their inhibitors contributeto inflammatory skin diseases. Arch ImmunolTher Exp 57:345–54

Mitsuhashi Y, Hashimato I (1989) Keratosis palmo-plantaris Nagashima. Dermatologica 179:231

Miyata T, Inagi R, Nangaku M et al. (2002) Over-expression of the serpin megsin inducesprogressive mesangial cell proliferation andexpansion. J Clin Invest 109:585–93

Nagashima M (1977) Palmoplantar keratoses. In:Miura O, Ochiai K (eds). Handbook ofHuman Genetics (in Japanese). Igaku Shoin:Tokyo, Japan, 23–7

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Yin J, Xu G, Wang H et al. (2014) Noveland recurrent SERPINB7 mutations inseven Chinese patients with Nagashima-typepalmoplantar keratosis. J Invest Dermatol134:2269–72

Zeeuwen PLJM, van Vlijmen-Willems IMJJ,Hendriks W et al. (2002) A null mutation inthe cystatin M/E gene of ichq mice causesjuvenile lethality and defects in epidermalcornification. Hum Mol Genet 11:2867–75

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