Nagashima-type palmoplantar keratosis in Finland caused by a SERPINB7 founder mutation
Authors: Katariina Hannula-Jouppi, Liisa Harjama, Elisabet Einarsdottir, Outi Elomaa, Kaisa Kettunen, Janna Saarela, Minna Soronen, Laura Bouchard, Katriina Lappalainen, Hannele Heikkilä, Sirpa Kivirikko, Mikko R.J. Seppänen, Juha Kere, Annamari Ranki
Journal: Journal of the American Academy of Dermatology (2019)

To the Editor: Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive PPK caused by mutations in the serpin family B member 7 (SERPINB7) gene.1Kubo 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 (74) Google Scholar It has been reported only in Japanese, Chinese, and Korean populations, with a common founder mutation c.796C>T p.(Arg266∗).1Kubo 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 (74) Google Scholar, 2Zhang J. Zhang G. Ni C. et al.Nagashima-type palmoplantar keratosis in a Chinese Han population.Mol Med Rep. 2016; 14: 4049-4054Crossref PubMed Scopus (8) Google Scholar, 3On H.R. Lee S.E. Nomura T. et al.Identification of SERPINB7 mutations in Korean patients with Nagashima-type palmoplantar keratosis.J Dermatol. 2017; 44: 840-841Crossref PubMed Scopus (5) Google Scholar NPPK is characterized by well-demarcated, mild, nonprogressive, diffuse hyperkeratosis with transgradient erythema expanding onto the dorsal aspect of the hands, wrists, and Achilles tendon area. Palmoplantar hyperhidrosis, aquagenic whitening, and fungal infections are frequent.1Kubo 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 (74) Google Scholar,4Yin J. Xu G. Wang H. et al.New and recurrent SERPINB7 mutations in seven Chinese patients with Nagashima-type palmoplantar keratosis.J Invest Dermatol. 2014; 134: 2269-2272Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Loss of functional SERPINB7 in skin probably leads to overactivation of intracorneocyte proteases causing skin barrier defects with hyperkeratosis, mild inflammation, and increased water permeability.1Kubo 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 (74) Google Scholar We report 3 non-Asian patients with NPPK, with a typical NPPK phenotype and homozygous SERPINB7 mutation. Since the age of 2 months, the 27-year-old Finnish male proband (P1) had a mild diffuse PPK with a well-demarcated erythema extending to the wrist and Achilles tendon area (Fig 1, Table I). His whole exome sequencing (Supplemental Text 1, available at Mendeley doi: 10.17632/z8tjpfdj3v.1) revealed a homozygous SERPINB7 c.1136G>A p.(Cys379Tyr) (NM_003784.3) variant (rs201208667) in exon 8 encoding the second-last amino acid of SERPINB7. His unaffected mother and sister were heterozygous carriers of the variant.Table IClinical characteristics of the patientsVariableP1P2P3P4P5P6P7P1 motherP1 sisterNPPKSERPINB7 c.1136G>A (rs201208667)A/AA/AA/AG/AG/AG/AG/AG/AG/A−Whole exome sequencing∗Whole exome sequencing: +, done; −, not done.+−−+++−−−Age, y271811602112166632SexMaleMaleMaleMaleFemaleFemaleMaleFemaleFemaleAge of onset2 moBirth1.5 yEarly childhoodEarly childhoodBirth9 y−−Birth to 9-10 yDiffuse mild PPK+++++++−−+Transgradients+++++++−−+Achilles tendon affected+++−++−−−+Wrists affected+++−++−−−+Progrediens−−−−−−−−−−Hyperhidrosis+++++++−−+/−Aquagenic whitening+++N/A++−−−+Fungal infections+−−−+++−−+Knee/elbow hyperkeratosis−−−−−−−−−+/−+, Present; −, not present; N/A, not applicable; NPPK, Nagashima-type palmoplantar keratosis; P, patient; PPK, palmoplantar keratosis.∗ Whole exome sequencing: +, done; −, not done. Open table in a new tab +, Present; −, not present; N/A, not applicable; NPPK, Nagashima-type palmoplantar keratosis; P, patient; PPK, palmoplantar keratosis. Sanger sequencing among 44 unrelated Finnish patients with PPK revealed 2 other homozygous patients and 4 heterozygous carriers (Table I). Whole exome sequencing of 3 heterozygous patients (P4, P5, and P6) revealed no other likely pathogenic variants or copy-number variations in SERPINB7 or other genes. Whole exome sequencing was unfeasible for P7, but a single nucleotide polymorphism array for haplotype analysis revealed no other SERPINB7 variants or copy-number variations. The cause of their PPK thus remains unknown. Other plausible SERPINB7 variants were not analyzed in the other patients. SERPINB7 c.1136G>A p.(Cys379Tyr) has not been reported in NPPK (Supplemental Table 1, available at Mendeley doi: 10.17632/z8tjpfdj3v.1). It was predicted damaging by Sorting Intolerant From Tolerant (SIFT), Polymorphism Phenotyping (PolyPhen), MutationTaster, logistic regression test (LRT), and Combined Annotation Dependent Depletion (CADD) (score 19). Only heterozygous carriers were found in population allele frequency databases (Exome Aggregation Consortium [ExAC], Genome Aggregation Database [GnomAD], and Sequencing Initiative Suomi [SISu]). According to GnomAD, the heterozygous carrier frequency was significantly higher for the Finnish population (0.006397) than for non-Finns (0.00032-0.0014), indicating a 5- to 20-fold enrichment in Finns. A common haplotype spanning 272 kilobase (kb) around the detected variant was shared by P1, P2, and 6 heterozygous carriers, according to genome-wide single nucleotide polymorphism array data (Supplemental Table 2, available at Mendeley doi: 10.17632/z8tjpfdj3v.1). The variant thus constitutes a plausible Finnish NPPK founder mutation. The skin histology of P1 showed nonepidermolytic hyperkeratosis compatible with NPPK. SERPINB7 immunostaining was strong throughout the stratum spinosum, with the most intense staining in the stratum granulosum. Heterozygous carriers and healthy controls showed less intense staining throughout the stratum spinosum and the lower stratum spinosum was negative (Supplemental Fig 1, available at Mendeley doi: 10.17632/z8tjpfdj3v.1). Thus, the c.1136G>A p.(Cys379Tyr) mutation apparently leads to aberrant SERPINB7 distribution within the stratum spinosum. The c.1136G>A p.(Cys379Tyr) SERPINB7 variant changes the second-last amino acid cysteine, which is conserved among different species (Supplemental Fig 2, available at Mendeley doi: 10.17632/z8tjpfdj3v.1). Tertiary structure prediction suggested that the substitution is in the vicinity of the reactive site loop where most SERPINB7 mutations in NPPK are located. The substitution possibly affects the conformational mobility of the reactive site loop during the inhibition process.5Gettins P.G. Olson S.T. Inhibitory serpins. New insights into their folding, polymerization, regulation and clearance.Biochem J. 2016; 473: 2273-2293Crossref PubMed Scopus (49) Google Scholar Previously NPPK has been reported exclusively in Asian patients. Our findings encourage assessment for SERPINB7 mutations in non-Asian individuals with an NPPK-phenotype. All patients and their families are thanked for participation. Alli Tallqvist, Eira Leinonen, and Auli Saarinen are thanked for their expertise in the laboratory. The Department of Dermatology, Helsinki University Central Hospital is a health care provider of the European Reference Network ERN-Skin.