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Mutations in SERPINB7, Encoding a Member of the Serine Protease Inhibitor Superfamily, Cause Nagashima-type Palmoplantar Keratosis  Akiharu Kubo, Aiko.

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Presentation on theme: "Mutations in SERPINB7, Encoding a Member of the Serine Protease Inhibitor Superfamily, Cause Nagashima-type Palmoplantar Keratosis  Akiharu Kubo, Aiko."— Presentation transcript:

1 Mutations in SERPINB7, Encoding a Member of the Serine Protease Inhibitor Superfamily, Cause Nagashima-type Palmoplantar Keratosis  Akiharu Kubo, Aiko Shiohama, Takashi Sasaki, Kazuhiko Nakabayashi, Hiroshi Kawasaki, Toru Atsugi, Showbu Sato, Atsushi Shimizu, Shuji Mikami, Hideaki Tanizaki, Masaki Uchiyama, Tatsuo Maeda, Taisuke Ito, Jun-ichi Sakabe, Toshio Heike, Torayuki Okuyama, Rika Kosaki, Kenjiro Kosaki, Jun Kudoh, Kenichiro Hata, Akihiro Umezawa, Yoshiki Tokura, Akira Ishiko, Hironori Niizeki, Kenji Kabashima, Yoshihiko Mitsuhashi, Masayuki Amagai  The American Journal of Human Genetics  Volume 93, Issue 5, Pages (November 2013) DOI: /j.ajhg Copyright © 2013 The American Society of Human Genetics Terms and Conditions

2 Figure 1 Family Pedigrees and Skin Manifestations of the Probands with NPPK (A) Pedigrees for the families in which exome sequencing and analyses were performed on the probands (KDex8, KDex14, and KDex20). Segregation of the mutations identified in each pedigree is shown. (B) Skin manifestations of the proband KDex14. (C) Hematoxylin and eosin staining of the plantar epidermis of the proband KDex8. Scale bars represent 100 μm. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

3 Figure 2 Genomic Organization of SERPINB7, Reactive Site Loop for Protease Inhibitory Activity of the SERPINB7 Protein, and Location of NPPK-Causing Mutations (A) Schematic presentation of the genomic structure of SERPINB7 (lower) and its encoded protein (middle), SERPINB7. The gray box indicates the reactive site loop indispensable for protease inhibitory activity of SERPINB7. Open and filled boxes indicate exons of untranslated regions and coding regions, respectively. The positions of SERPINB7 mutations identified in this study are indicated. The immunogen of the anti-SERPINB7 polyclonal antibody is shown at the top. (B) Heterozygous or homozygous mutated sequences of affected individuals (KDex8, KDex14, and KDex20) compared with the corresponding wild-type sequences. The base and amino acid sequences are shown. The intron-exon junctions are shown with red dotted lines. Intron and exon sequences are shown in lower case and upper case, respectively. Abbreviations are as follows: c.218_219 del2ins12, c.218_219delAGinsTAAACTTTACCT. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

4 Figure 3 SERPINB7 Localization in the Epidermis and Immunohistochemical Analysis of the Affected Skin (A) Investigation of the anti-SERPINB7 antibody. GST-fused recombinant full-length human SERPINB7 (lanes 1 and 3) and GST-fused recombinant p.Arg266∗ mutant (lanes 2 and 4) were analyzed by electrophoresis with Coomassie Brilliant Blue staining (lanes 1 and 2) or with immunoblotting with the anti-SERPINB7 rabbit polyclonal antibody (lanes 3 and 4). Scale bars indicate molecular weights (kDa). (B) Immunohistochemistry of SERPINB7 in plantar skin of a healthy control. Upper panel shows SERPINB7 in the stratum granulosum (arrow) and in the upper part of the stratum corneum (arrowhead). Lower panel shows the intracellular distribution of SERPINB7 in the stratum granulosum. Scale bars represent 100 μm. Inset in the lower panel shows stratum granulosum cells and intercellular spaces at higher magnification (scale bar represents 50 μm). (C) Immunohistochemistry of SERPINB7 in the hyperkeratotic plantar skin of NPPK individual of KDex8. Scale bar represents 100 μm. (D) Immunohistochemistry of SERPINB7 in facial and abdominal skin sections of a healthy control. Scale bars represent 100 μm. (E) Immunohistochemistry of epidermal differentiation-related proteins in plantar skin of a healthy control (upper panels) and a NPPK individual (KDex8; lower panels). Scale bar represents 100 μm. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

5 Figure 4 Changes upon Water Exposure in NPPK Lesional Skin
(A) Clinical phenotype of the hands of the proband (KDex8) prior to water exposure (upper left panel) and after 10 min water exposure (upper right panel), and the clinical phenotype of the hands of the proband (KDex14) after 30 min water exposure: the palm (lower left panel), inner wrist (lower middle panel), and dorsa of the thumb (lower right panel). (B) Means of TEWL values prior to water exposure and after 30 min of water exposure in the lesional skin and nonlesional skin of NPPK individuals (n = 3; KDex8, KDex14, and KDex79) and in the corresponding skin area of healthy controls (n = 3). In each skin condition, the means of TEWL were compared upon water exposure (lower lines). The means of TEWL were compared between lesional and nonlesional skin of NPPK individuals and the corresponding skin area of healthy controls before water exposure (upper black lines) and after water exposure (upper red lines). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

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