Nagashima-Type Palmoplantar Keratosis: A Common Asian Type Caused by SERPINB7 Protease Inhibitor Deficiency

Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive diffuse non-epidermolytic palmoplantar keratosis caused by mutations in SERPINB7, a member of the serine protease inhibitor superfamily. Genetic studies suggest that NPPK 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 a founder effect of a SERPINB7 mutation in Chinese populations. Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive diffuse non-epidermolytic palmoplantar keratosis caused by mutations in SERPINB7, a member of the serine protease inhibitor superfamily. Genetic studies suggest that NPPK 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 a founder effect of a SERPINB7 mutation in Chinese populations. Nagashima-type palmoplantar keratosis (NPPK; MIM 615598) is a comparatively new entity of palmoplantar keratosis (PPK). Masaji Nagashima first described this disease briefly in 1977 as a form of PPK showing a similar distribution of lesions to, but a considerably milder disease phenotype than, Mal de Meleda (MIM 248300) (Nagashima, 1977Nagashima M. Palmoplantar keratoses.in: Miura O. K Ochiai Handbook of Human Genetics (in Japanese). Igaku Shoin, Tokyo, Japan1977: 23-27Google Scholar). Independently, Mitsuhashi and Hashimato, 1989Mitsuhashi Y. Hashimato I. Keratosis palmoplantaris Nagashima.Dermatologica. 1989; 179: 231Google Scholar observed a Japanese patient who had reddish diffuse mild PPK extending to the dorsal surfaces of the hands and feet. Together with UW Schnyder, a Swiss specialist in genetic skin diseases who investigated Mal de Meleda in the Adriatic island of Mljet (Meleda) (Schnyder, 1969Schnyder U.W. Meleda expedition 1968 (in German).Hautarzt. 1969; 20: 285-286PubMed Google Scholar), they concluded that the patient's phenotype was far milder than that of Mal de Meleda. Ultimately, they reported siblings with the same distinct disease phenotype and concluded that the disease was a novel autosomal recessive PPK, designating it as "keratosis palmoplantaris Nagashima" (Mitsuhashi and Hashimato, 1989Mitsuhashi Y. Hashimato I. Keratosis palmoplantaris Nagashima.Dermatologica. 1989; 179: 231Google Scholar). Because of its probable very low prevalence in Western countries, this disease entity has long been recognized only in Japan. In 2008, Kabashima et al., 2008Kabashima K. Sakabe J. Yamada Y. et al."Nagashima-type" keratosis as a novel entity in the palmoplantar keratoderma category.Arch Dermatol. 2008; 144: 375-379Crossref PubMed Scopus (44) Google Scholar introduced NPPK to international societies with a detailed description of the disease phenotype, and they proposed NPPK as a distinct clinical entity because of the lack of mutations in the exonic region of SLURP1, the causative gene of Mal de Meleda. In 2013, Kubo et al., 2013Kubo A. Shiohama A. Sasaki T. et al.Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis.Am J Hum Genet. 2013; 93: 945-956Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar finally identified the causative gene mutations as residing in SERPINB7, a member of the serine protease inhibitor superfamily, in 13 unrelated Japanese NPPK patients via exome sequencing, and they established NPPK as a novel disease entity. As the major causative mutation, c.796C>T (p.R266*) in SERPINB7, was found in 8/286 Japanese and Chinese individuals in the 1000 Genomes Database (http://browser.1000genomes.org), the mutation has been proposed to be distributed widely among Asian populations (Kubo et al., 2013Kubo A. Shiohama A. Sasaki T. et al.Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis.Am J Hum Genet. 2013; 93: 945-956Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). In this issue, Yin et al. now characterize NPPK patients from China, and they confirm the founder effect of the c.796C>T mutation in SERPINB7 among a second Asian population. NPPK is characterized clinically by well-demarcated reddish, diffuse, and mild palmoplantar non-epidermolytic hyperkeratosis that extends to the dorsal surfaces of the hands and feet, inner wrists, ankles, and the Achilles tendon area (Figure 1). High frequencies of hyperhidrosis on palms and soles and tinea infection have been noted. The affected areas and clinical manifestations are non-progressive, which is the major clinical difference from Mal de Meleda. The palms and soles of NPPK patients show a whitish spongy appearance within 10 minutes of water exposure specifically in the reddish hyperkeratotic area (Figure 1c and d; Kubo et al., 2013Kubo A. Shiohama A. Sasaki T. et al.Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis.Am J Hum Genet. 2013; 93: 945-956Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar; Yin et al., 2014Yin J. Xu G. Wang H. et al.Novel and recurrent SERPINB7 mutations in seven Chinese patients with Nagashima-type palmoplantar keratosis.J Invest Dermatol. 2014; https://doi.org/10.1038/jid.2014.80Abstract Full Text Full Text PDF Scopus (34) Google Scholar). Whitish changes in the palms and soles after water exposure have also been reported in autosomal dominant Bothnian-type PPK (MIM 600231) caused by AQP5 mutations. Yin et al. investigated the seven Chinese PPK patients with reddish mild hyperkeratosis showing whitish spongy changes after water exposure and showed that all seven patients had bi-allelic mutations in SERPINB7, but not in AQP5. Taken together with the fact that 9 causative mutations in SERPINB7 but no causative mutations in AQP5 were found in 286 Japanese and Chinese individuals in the 1000 Genomes Database, NPPK is suggested to be more common than Bothnian-type PPK in Japanese and Chinese populations. As other types of PPK have considerably lower prevalences, NPPK is likely the most common type of PPK in Asian populations. Among SERPINB7 mutations in NPPK, 10 of the 14 alleles of Chinese patients and 19 of the 26 alleles of Japanese patients were c.796C>T (Kubo et al., 2013Kubo A. Shiohama A. Sasaki T. et al.Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis.Am J Hum Genet. 2013; 93: 945-956Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar; Yin et al., 2014Yin J. Xu G. Wang H. et al.Novel and recurrent SERPINB7 mutations in seven Chinese patients with Nagashima-type palmoplantar keratosis.J Invest Dermatol. 2014; https://doi.org/10.1038/jid.2014.80Abstract Full Text Full Text PDF Scopus (34) Google Scholar). Haplotype analysis in Chinese patients suggested that c.796C>T is a founder mutation, instead of a mutation hotspot (Yin et al., 2014Yin J. Xu G. Wang H. et al.Novel and recurrent SERPINB7 mutations in seven Chinese patients with Nagashima-type palmoplantar keratosis.J Invest Dermatol. 2014; https://doi.org/10.1038/jid.2014.80Abstract Full Text Full Text PDF Scopus (34) Google Scholar). The c.796C>T mutation was not found in 806 individuals of non-Asian origin in the 1000 Genomes Database or 12,517 alleles of European-American and African-American origin in the NHBLI Exome Variant Server (http://evs.gs.washington.edu/EVS/). These results indicates that the c.796C>T mutation has spread widely among Asian populations due to its founder effect, which explains why NPPK is so common in Japan and probably in China but has not been reported in Western countries. SERPINB7 is a member of the SERine Protease INhibitor (Serpin) superfamily. Human serpins have been divided into nine clades (A-I). In general, protease inhibitors are resistant to protease-dependent degradation. If they are sensitive to proteases, it is not possible for them to function as protease inhibitors. As stable as they are, some serpins have lost their protease inhibitory activities during the course of evolution, becoming storage proteins. For example, ovalbumin is a homolog of the clade B serpins, one that has lost its protease inhibitory activity. Therefore, clade B serpins, including SERPINB7, are alternatively known as ov-serpins. There are two major mechanisms by which mutations in SERPINs cause congenital diseases. One is that loss of protease inhibitory activity results in uncontrolled protease activity and tissue destruction. For example, deficiency of SERPINF2 (alpha2-antiplasmin) causes a bleeding disorder through uncontrolled plasmin activity and fibrinolysis (MIM 262850). The second mechanism is that formation of protease-resistant hyperstable misfolded polymers or aggregates of mutant serpins in serpin-synthesizing cells results in cell death and tissue damage. Such diseases are called "serpinopathies." For example, familial encephalopathy with neuroserpin inclusion bodies (MIM 604218) is a serpinopathy of SERPINI1 (neuroserpin) in which neurodegeneration is caused by aberrant protein processing and tissue deposition of SERPINI1 mutants. In some diseases, both mechanisms are involved. Deficiency of SERPINA1 (alpha1-antitrypsin) causes not only emphysema through proteolytic lung damage due to neutrophil elastase induced by the decreased plasma alpha1-antitrypsin level but also liver damage and cirrhosis through formation of hyperstable polymers of mutant alpha1-antitrypsin in the endoplasmic reticulum of liver cells (MIM 613490). Clade B serpins are intracellular serpins that possibly protect cells from exogenous and endogenous protease-mediated injury. SERPINB7 is expressed in the cytoplasm of stratum granulosum cells (Kubo et al., 2013Kubo A. Shiohama A. Sasaki T. et al.Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis.Am J Hum Genet. 2013; 93: 945-956Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Although the target protease of SERPINB7 has not been identified, the protease inhibitory activity of SERPINB7 has been demonstrated by plasmin inhibition assay (Miyata et al., 2002Miyata T. Inagi R. Nangaku M. et al.Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion.J Clin Invest. 2002; 109: 585-593Crossref PubMed Scopus (61) Google Scholar). In NPPK, inclusion bodies or protein aggregates have not been detected in the stratum granulosum or stratum corneum, suggesting that formation of mutated SERPINB7 polymers does not occur in NPPK patient skin. The reactive site loop indispensable for protease inhibitory activity is located at the C-terminus of SERPINB7 and is absent in all of the identified mutants due to the introduction of premature stop codons by nonsense, frameshift, or splice-site mutations. Therefore, NPPK is presumably caused by the loss of protease inhibitory activity of, and not polymer formation by, SERPINB7 in the epidermis.A widespread founder mutation in SERPINB7 causes NPPK as a common PPK in Asian populations. A widespread founder mutation in SERPINB7 causes NPPK as a common PPK in Asian populations. One of the characteristics of NPPK is the distribution of the reddish hyperkeratosis, extending to the dorsal surfaces of the hands and feet and Achilles tendon area, which is known as "transgrediens." SERPINB7 is expressed not only in palmoplantar skin but also in the skin of other body areas (Kubo et al., 2013Kubo A. Shiohama A. Sasaki T. et al.Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis.Am J Hum Genet. 2013; 93: 945-956Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). In several types of diffuse PPK with or without associated features, while the causative gene products have a widespread expression pattern, the disease is mostly restricted to the palmoplantar area. Although the mechanism of this discrepancy is as yet unknown, such PPKs include Vohwinkel syndrome (MIM 604117) caused by loricrin (LOR) mutations, PPK with deafness (MIM 148350) caused by connexin 26 (GJB2) mutations, and Mal de Meleda caused by SLURP1 mutations. Interestingly, these PPKs, as well as NPPK, show "transgrediens" to the dorsal surfaces of the hands and feet. By contrast, PPKs caused by mutations of palmoplantar-area-specific genes such as KRT9 (Vörner-type PPK (MIM 144200)) do not show such "transgrediens." Future studies will reveal the factor that restricts the affected area to the palms and soles mainly in NPPK, despite widespread expression of SERPINB7. Various proteases, including serine proteases, exist in the stratum granulosum and the stratum corneum: intracellular proteases, such as caspase 14, aspartic peptidase retroviral-like 1/SASPase, and bleomycin hydrolase responsible for filaggrin degradation; endolysosomal proteases, such as cystatins and cathepsins; secreted proteases, such as kallikreins and kallikrein-related peptidases responsible for desquamation; and transmembrane proteases, such as matriptase/suppression of tumorigenicity 14 (ST14) and prostatin/protease serine S1 family member 8 (PRSS8) (Meyer-Hoffert, 2009Meyer-Hoffert U. Reddish, scaly, and itchy: how proteases and their inhibitors contribute to inflammatory skin diseases.Arch Immunol Ther Exp. 2009; 57: 345-354Crossref PubMed Scopus (110) Google Scholar; Ovaere et al., 2009Ovaere P. Lippens S. Vandenabeele P. et al.The emerging roles of serine protease cascades in the epidermis.Trends Biochem Sci. 2009; 34: 453-463Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). Additionally, the epidermis is attacked by various exogenous proteases, originating from bacteria, fungi, viruses, pollen, and house dust mites, and endogenous proteases such as neutrophil elastase and mast cell chymase, originating from infiltrating cells. It is likely that the epidermis expresses various protease inhibitors, such as LEKTI, LEKTI-2, secretory leukocyte protease inhibitor, elafin/skin-derived protease inhibitor, serpins, and cystatins, to control the activity of these proteases (Meyer-Hoffert, 2009Meyer-Hoffert U. Reddish, scaly, and itchy: how proteases and their inhibitors contribute to inflammatory skin diseases.Arch Immunol Ther Exp. 2009; 57: 345-354Crossref PubMed Scopus (110) Google Scholar). LEKTI deficiency results in Netherton syndrome (MIM 256500), in which overactivation of kallikreins and a Par2 signaling cascade have been demonstrated (Descargues et al., 2005Descargues P. Deraison C. Bonnart C. et al.Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity.Nat Genet. 2005; 37: 56-65Crossref PubMed Scopus (306) Google Scholar; Deraison et al., 2007Deraison C. Bonnart C. Lopez F. et al.LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction.Mol Biol Cell. 2007; 18: 3607-3619Crossref PubMed Scopus (247) Google Scholar; Briot et al., 2009Briot A. Deraison C. Lacroix M. et al.Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome.J Exp Med. 2009; 206: 1135-1147Crossref PubMed Scopus (396) Google Scholar). Studies of transgenic mice with induced overexpression of Prss8 or Par2 reported skin inflammatory responses and ichthyosis (Frateschi et al., 2011Frateschi S. Camerer E. Crisante G. et al.PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin.Nat Commun. 2011; 2: 161Crossref PubMed Scopus (85) Google Scholar). Knockout mouse studies targeting proteases (Prss8, matriptase/St14, and caspase 14) or protease inhibitors (Spink5/LEKTI and cystatin E/M) showed skin barrier deficiencies and/or inflammation (List et al., 2002List K. Haudenschild C.C. Szabo R. et al.Matriptase/MT-SP1 is required for postnatal survival, epidermal barrier function, hair follicle development, and thymic homeostasis.Oncogene. 2002; 21: 3765-3779Crossref PubMed Scopus (282) Google Scholar; Zeeuwen et al., 2002Zeeuwen P.L.J.M. van Vlijmen-Willems I.M.J.J. Hendriks W. et al.A null mutation in the cystatin M/E gene of ichq mice causes juvenile lethality and defects in epidermal cornification.Hum Mol Genet. 2002; 11: 2867-2875Crossref PubMed Google Scholar; Leyvraz et al., 2005Leyvraz C. Charles R.-P. Rubera I. et al.The epidermal barrier function is dependent on the serine protease CAP1/Prss8.J Cell Biol. 2005; 170: 487-496Crossref PubMed Scopus (233) Google Scholar; Descargues et al., 2005Descargues P. Deraison C. Bonnart C. et al.Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity.Nat Genet. 2005; 37: 56-65Crossref PubMed Scopus (281) Google Scholar; Denecker et al., 2007Denecker G. Hoste E. Gilbert B. et al.Caspase-14 protects against epidermal UVB photodamage and water loss.Nat Cell Biol. 2007; 9: 666-674Crossref PubMed Scopus (232) Google Scholar). Thus, appropriate control of the activity of these proteases is likely important in maintaining skin homeostasis. However, their regulatory mechanisms remain mostly unknown. The discovery of loss-of-function mutations in SERPINB7 in NPPK should provide insight into the functions and regulatory mechanisms of proteases and protease inhibitors in the epidermis.