An establishment of tailor-made treatments for the patients with inherited keratinization disorders

• Project/Area Number: 16K19717
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Nagoya University
• Principal Investigator: Takeichi Takuya 名古屋大学, 医学部附属病院, 助教 (30754931)
• Research Collaborator: AKIYAMA Masashi ; SUGIURA Kazumitsu
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 遺伝性角化症 / 皮膚遺伝学 / 遺伝学

Outline of Final Research Achievements

According to the research plan, we performed molecular biological analysis including whole exome sequencing analysis using samples of 50 familiy of hereditary keratinyzation disorders including congenital ichthyosis and palmoplantar keratoderma. As results, reported pathogenic mutations (e.g. SDR9C7 and PHGDH) have been identified in several families. In addition, we have reported that biallelic mutations in KDSR are implicated in an extended spectrum of disorders of keratinization in which thrombocytopenia is also part of the phenotype. Mutations in KDSR cause defective ceramide biosynthesis, underscoring the importance of ceramide and sphingosine synthesis pathways in skin and platelet biology.

Academic Significance and Societal Importance of the Research Achievements

本研究により、多くの遺伝性角化症の患者の病因遺伝子を同定し、その病態を解明することができた。中でも、SDR9C7遺伝子変異を持つ患者において、角層細胞間脂質の減少と層板顆粒内の層状構造物の減少を発見することができた。これは世界でも2番目の、SDR9C7遺伝子による先天性魚鱗癬様紅皮症の報告になり、本報告により、他の日本人の魚鱗癬患者の中にも、この遺伝子の異常で疾患が引き起こされている患者がいることが示唆された。遺伝子型-表現型の解析がさらに進めば、オーダーメイド治療の開発に繋がることが期待される。

Research Products

• [Int'l Joint Research] キングスカレッジロンドン(英国)
• [Int'l Joint Research] キングスカレッジロンドン(英国)
• [Journal Article] Familial or sporadic porokeratosis as an autoinflammatory keratinization disease. (2019)
  • Author(s): Takeichi T, Akiyama M.
  • Journal Title: J Dermatol. Volume: 46 Issue: 4
  • DOI: 10.1111/1346-8138.14666
  • NAID: 120006652416
  • Peer Reviewed
• [Journal Article] Acrodermatitis continua of Hallopeau with dense infiltration of IgG4-positive cells in the lesional dermis. (2019)
  • Author(s): Ogawa-Momohara M, Muro Y, Nakaguro M, Takeichi T, Kono M, Akiyama M.
  • Journal Title: Br J Dermatol. Volume: 180 Issue: 4 Pages: 941-942
  • DOI: 10.1111/bjd.17405
  • Peer Reviewed
• [Journal Article] Aberrant CARD14 function might cause defective barrier formation. (2019)
  • Author(s): Murase Y, Takeichi T, Akiyama M.
  • Journal Title: J Allergy Clin Immunol. Volume: 143 Issue: 4 Pages: 1656-1657
  • DOI: 10.1016/j.jaci.2018.11.044
  • NAID: 120006652417
  • Peer Reviewed
• [Journal Article] Multiple keratotic papules and plaques on the trunk in Cowden’s disease with MALT lymphoma. (2018)
  • Author(s): Mizuno S, Takeichi T, Sato J, Nakamura M, Goto H, Sugiura K, Akiyama M.
  • Journal Title: J Dermatol Volume: 45 Issue: 2 Pages: 238-240
  • DOI: 10.1111/1346-8138.13851
  • NAID: 120006473545
  • Peer Reviewed
• [Journal Article] Trichothiodystrophy, complementation group A complicated with squamous cell carcinoma. (2018)
  • Author(s): Takeichi T, Tomimura S, Okuno Y, Hamada M, Kono M, Sugiura K, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Volume: 32 Issue: 2
  • DOI: 10.1111/jdv.14531
  • Peer Reviewed
• [Journal Article] A novel IFIH1 mutation in the pincer domain underlies the clinical features of both Aicardi-Goutières and Singleton-Merten syndromes in a single patient. (2018)
  • Author(s): Takeichi T, Katayama C, Tanaka T, Okuno Y, Murakami N, Kono M, Sugiura K, Aoyama Y, Akiyama M.
  • Journal Title: Br J Dermatol Volume: 178 Issue: 2 Pages: e111-e113
  • DOI: 10.1111/bjd.15869
  • Peer Reviewed
• [Journal Article] Autoinflammatory keratinization diseases: an emerging concept encompassing various inflammatory keratinization disorders of the skin. (2018)
  • Author(s): Akiyama M, Takeichi T, McGrath JA, Sugiura K.
  • Journal Title: J Dermatol Sci Volume: 90 Issue: 2 Pages: 105-111
  • DOI: 10.1016/j.jdermsci.2018.01.012
  • NAID: 120006517661
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] An infant with generalized pustular psoriasis and geographic tongue had a heterozygous IL36RN mutation and IgG2 deficiency. (2018)
  • Author(s): Oi R, Takeichi T, Okuno Y, Kojima D, Sugawara K, Kono M, Muramatsu H, Akiyama M
  • Journal Title: J Dermatol Sci. Volume: 印刷中 Issue: 2 Pages: 216-218
  • DOI: 10.1016/j.jdermsci.2018.01.017
  • Peer Reviewed
• [Journal Article] Deficiency of the interleukin-36 receptor antagonist dramatically improved by secukinumab. (2018)
  • Author(s): Kinoshita M, Okamoto T, Sano S, Mitsui H, Takeichi T, Sugiura K, Akiyama M, Shimada S, Kawamura T.
  • Journal Title: J Dermatol Volume: 45 Issue: 10
  • DOI: 10.1111/1346-8138.14330
  • Peer Reviewed
• [Journal Article] Hearing impairment; a secondary symptom in a congenital ichthyosiform erythroderma patient with ABCA12 mutations. (2018)
  • Author(s): Murase C, Takeichi T, Sugiura K, Kobayashi M, Shiomi K, Ikebuchi K, Akiyama M.
  • Journal Title: J Dermatol Volume: 45 Issue: 11
  • DOI: 10.1111/1346-8138.14350
  • Peer Reviewed
• [Journal Article] Sterol profiles are valuable biomarkers for phenotype expression of Conradi-Hünermann-Happle syndrome with EBP mutations. (2018)
  • Author(s): Takeichi T, Honda A, Okuno Y, Kojima D, Kono M, Nakamura Y, Tohyama M, Tanaka T, Aoyama Y, Akiyama M.
  • Journal Title: Br J Dermatol. Volume: 179 Issue: 5 Pages: 1186-1188
  • DOI: 10.1111/bjd.16823
  • Peer Reviewed
• [Journal Article] Impetigo herpetiformis with IL-36RN mutation successfully treated with secukinumab. (2018)
  • Author(s): Kinoshita M, Ogawa Y, Takeichi T, Okamoto T, Osada A, Shimada S, Sugiura K, Akiyama M, Kawamura T, Tsukamoto K.
  • Journal Title: Eur J Dermatol. Volume: 28 Issue: 3 Pages: 381-382
  • DOI: 10.1684/ejd.2018.3259
  • Peer Reviewed
• [Journal Article] Roles of aberrant hemichannel activities due to mutant connexin26 in the pathogenesis of KID syndrome. (2018)
  • Author(s): Taki T, Takeichi T, Sugiura K, Akiyama M.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 12824-12824
  • DOI: 10.1038/s41598-018-30757-3
  • Peer Reviewed / Open Access
• [Journal Article] Cross-sectional survey on disease severity in Japanese patients with harlequin ichthyosis/ichthyosis: Syndromic forms and quality-of-life analysis in a subgroup (2018)
  • Author(s): Murase C, Takeichi T, Shibata A, Nakatochi M, Kinoshita F, Kubo A, Nakajima K, Ishii N, Amano H, Masuda K, Kawakami H, Kanekura T, Washio K, Asano M, Teramura K, Akasaka E, Tohyama M, Hatano Y, Ochiai T, Moriwaki S, Sato T, Ishida-Yamamoto A, Seishima M, Kurosawa M, Ikeda S, Akiyama M.
  • Journal Title: J Dermatol Sci. Volume: 92 Issue: 2 Pages: 127
  • DOI: 10.1016/j.jdermsci.2018.08.008
  • NAID: 120006623824
  • Peer Reviewed
• [Journal Article] Reduction of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate dehydrogenase deficiency. (2018)
  • Author(s): Reduction of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate dehydrogenase deficiency.
  • Journal Title: Journal of lipid research Volume: 59 Issue: 12 Pages: 2413-1420
  • DOI: 10.1194/jlr.p087536
  • Peer Reviewed
• [Journal Article] 悪性黒色腫を生じた魚鱗癬の1例 (2018)
  • Author(s): 辻由貴子、大湖健太郎、藤岡 愛、木戸一成、中島喜美子、中島英貴、佐野栄紀、武市拓也、秋山真志
  • Journal Title: 角化症研究会記録集 Volume: 32 Pages: 57-59
• [Journal Article] 【最近のトピックス2018】皮膚疾患の病態 遺伝性角化症における復帰変異 (2018)
  • Author(s): 武市拓也
  • Journal Title: 臨床皮膚科 Volume: 72 Pages: 51-54
• [Journal Article] 知っておきたい基礎用語 自己炎症性角化症 (2018)
  • Author(s): 武市拓也
  • Journal Title: 日本小児皮膚科学会雑誌 Volume: 37 Pages: 50-51
• [Journal Article] Case of mild X-linked ichthyosis complicated with paroxysmal supraventricular tachycardia and anemia. (2018)
  • Author(s): Maki Y, Takeichi T, Kono M, Tanaka Y, Akiyama M.
  • Journal Title: J Dermatol. Volume: - Issue: 10
  • DOI: 10.1111/1346-8138.14307
  • Peer Reviewed
• [Journal Article] Congenital ichthyosis and recurrent eczema associated with a novel ALOXE3 mutation. (2017)
  • Author(s): Takeichi T, Okuno Y, Saito C, Kojima D, Kono M, Morita A, Sugiura K, Akiyama M.
  • Journal Title: Acta Dermato-Venereol Volume: 97(4) Issue: 4 Pages: 532-533
  • DOI: 10.2340/00015555-2549
  • Peer Reviewed / Open Access
• [Journal Article] A case of lamellar ichthyosis due to a novel TGM1 mutation associated with Parkinson's disease. (2017)
  • Author(s): Morita-Adachi R, Takeichi T, Okuno Y, Kataoka S, Hoshino S, Akiyama M.
  • Journal Title: Eur J Dermatol. Volume: 27 Issue: 4 Pages: 438-439
  • DOI: 10.1684/ejd.2017.3049
  • NAID: 120006375881
  • Peer Reviewed
• [Journal Article] Deficient stratum corneum intercellular lipid in a Japanese patient with lamellar ichthyosis by a homozygous deletion mutation in SDR9C7. (2017)
  • Author(s): Takeichi T, Nomura T, Takama H, Kono M, Sugiura K, Watanabe D, Shimizu H, Simpson MA, McGrath JA, Akiyama M.
  • Journal Title: Br J Dermatol Volume: 印刷中 Issue: 3
  • DOI: 10.1111/bjd.15315
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autosomal dominant familial generalized pustular psoriasis caused by a CARD14 mutation. (2017)
  • Author(s): Takeichi T, Kobayashi A, Ogawa E, Okuno Y, Kataoka S, Kono M, Sugiura K, Okuyama R, Akiyama M.
  • Journal Title: Br J Dermatol. Volume: 177 Issue: 4 Pages: e133-e135
  • DOI: 10.1111/bjd.15442
  • Peer Reviewed
• [Journal Article] A combination of low-dose systemic etretinate and topical calcipotriol/betamethasone dipropionate treatment for hyperkeratosis and itching in Olmsted syndrome associated with a TRPV3 mutation. (2017)
  • Author(s): Takeichi T, Tsukamoto K, Okuno Y, Kojima D, Kono M, Suga Y, Akiyama M.
  • Journal Title: J Dermatol Sci. Volume: 88 Issue: 1 Pages: 144-146
  • DOI: 10.1016/j.jdermsci.2017.05.012
  • NAID: 120006382254
  • Peer Reviewed
• [Journal Article] Biallelic Mutations in KDSR Disrupt Ceramide Synthesis and Result in a Spectrum of Keratinization Disorders Associated with Thrombocytopenia. (2017)
  • Author(s): Takeichi T, Torrelo A, Lee JYW, Ohno Y, Lozano ML, Kihara A, Liu L, Yasuda Y, Ishikawa J, Murase T, Rodrigo AB, Fernández-Crehuet P, Toi Y, Mellerio J, Rivera J, Vicente V, Kelsell DP, Nishimura Y, Okuno Y, Kojima D, Ogawa Y, Sugiura K, Simpson MA, McLean WHI, Akiyama M, McGrath JA.
  • Journal Title: J Invest Dermatol. Volume: 137 Issue: 11 Pages: 2344-2353
  • DOI: 10.1016/j.jid.2017.06.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Granulocyte and monocyte apheresis can control juvenile generalized pustular psoriasis with mutation of IL36RN. (2017)
  • Author(s): Koike Y, Okubo M, Kiyohara T, Fukuchi R, Sato Y, Kuwatsuka S, Takeichi T, Akiyama M, Sugiura K, Utani A.
  • Journal Title: Br J Dermatol. Volume: 177 Issue: 6 Pages: 1732-1736
  • DOI: 10.1111/bjd.15509
  • Peer Reviewed
• [Journal Article] Autoinflammatory keratinization diseases. (2017)
  • Author(s): Akiyama M, Takeichi T, McGrath JA, Sugiura K.
  • Journal Title: J Allergy Clin Immunol. Volume: 140 Issue: 6 Pages: 1545-1547
  • DOI: 10.1016/j.jaci.2017.05.019
  • NAID: 120006473509
  • Peer Reviewed
• [Journal Article] self-improving collodion ichthyosis (2017)
  • Author(s): 後藤克修, 武市拓也, 菅原由実菜, 秋山真志
  • Journal Title: 皮膚病診療 Volume: 39 Pages: 869-872
  • Peer Reviewed
• [Journal Article] 指定難病最前線(Volume45) 先天性魚鱗癬の特徴と診療の実際 (2017)
  • Author(s): 武市拓也, 秋山真志
  • Journal Title: 新薬と臨牀 Volume: 66 Pages: 1171-1175
• [Journal Article] A newly revealed IL36RN mutation in sibling cases complements our IL36RN mutation statistics for generalized pustular psoriasis. (2017)
  • Author(s): Takeichi T, Togawa Y, Taniguchi R, Okuno Y, Kono M, Matsue H, Sugiura K, Akiyama M.
  • Journal Title: J Dermatol Sci Volume: 85 Issue: 1 Pages: 58-60
  • DOI: 10.1016/j.jdermsci.2016.10.009
  • NAID: 120006305585
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Striate palmoplantar keratoderma showing transgrediens in a patient harboring heterozygous nonsense mutations in both DSG1 and SERPINB7. (2017)
  • Author(s): Fukaura R, Takeichi T, Okuno Y, Kojima D, Kono M, Sugiura K, Suga Y, Akiyama M.
  • Journal Title: Acta Derm Venereol Volume: 97 Issue: 3 Pages: 399-401
  • DOI: 10.2340/00015555-2553
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] A Nationwide Japanese Survey on Quality of Life and Disease Severity in Patients with Congenital Ichthyoses (2018)
  • Author(s): Chiaki Murase, Takuya Takeichi, Akitaka Shibata, Masahiro Nakatochi, Fumie Kinoshita, Shigaku Ikeda, Michiko Kurosawa, Masashi Akiyama
  • Organizer: IID 2018.
  • Int'l Joint Research
• [Presentation] ATP2A2遺伝子に新規変異を認めたダリエ病の1例 (2018)
  • Author(s): 寺田紗央里、武市拓也、安達明子、正木貞男、秋山真志
  • Organizer: 第283回日本皮膚科学会東海地方会
• [Presentation] ナローバンドUVBが有効であった変動性紅斑角皮症の1例 (2018)
  • Author(s): 奥田佳世子、西田絵美、鳥居 寛、松原章宏、佐川容子、武市拓也、秋山真志、森田明理
  • Organizer: 第283回日本皮膚科学会東海地方会
• [Presentation] 3歳で発症した尋常性乾癬 (2018)
  • Author(s): 村上めぐみ、日高友梨、水野絵里香、白井三由希、相山明輝、満間照之、加藤元一、武市拓也
  • Organizer: 第117回日本皮膚科学会総会
• [Presentation] Syndactyly type III and hypotrichosis in oculodentodigital syndrome with GJA1 mutation (2017)
  • Author(s): Tomoki Taki, Takuya Takeichi, Kazumitsu Sugiura, Masashi Akiyama
  • Organizer: The 76th Annual Meeting of the SID
  • Int'l Joint Research
• [Presentation] Strikingly predominance of LIPH founder mutations in autosomal recessive woolly hair and hypotrichosis in Japan. (2017)
  • Author(s): Kana Tanahashi, Takuya Takeichi, Tomoki Taki, Michihiro Kono, Kazumitsu Sugiura, Masashi Akiyama
  • Organizer: 10th World Congress for Hair Research
  • Int'l Joint Research
• [Presentation] DSG1とSERPINB7にヘテロの遺伝子変異を有する線状掌蹠角化症 (2017)
  • Author(s): 秋山真志、武市拓也、深浦 遼、河野通浩、奥野友介、小島大英、杉浦一充、須賀 康
  • Organizer: 第279回東海地方会
• [Presentation] NLRP1遺伝子変異によるfamilial keratosis lichenoides chronicaの一家系 (2017)
  • Author(s): 武市拓也、秋山真志、John A. McGrath
  • Organizer: 第32回角化症研究会
• [Presentation] ロリクリン角皮症の一例 (2017)
  • Author(s): 伊藤靖敏、武市拓也、秋山真志
  • Organizer: 第68回日本皮膚科学会中部支部学術大会
• [Presentation] Clinical associations in pityriasis rubra pilaris with underlying CARD14 mutations. (2016)
  • Author(s): Takuya Takeichi、Kazumitsu Sugiura、Toshifumi Nomura、Taiko Sakamoto、Yasushi Ogawa、Yasushi Suga、Hiroshi Shimizu、John A. McGrath、Masashi Akiyama
  • Organizer: 日本研究皮膚科学会第41回年次学術大会・総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-12-09
• [Presentation] Oculodentodigital syndrome diagnosed from hypotrichosis. (2016)
  • Author(s): Tomoki Taki、Takuya Takeichi、Kazumitsu Sugiura、Masashi Akiyama
  • Organizer: 日本研究皮膚科学会第41回年次学術大会・総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-12-09
• [Presentation] 毛孔性紅色粃糠疹の臨床学的特徴 (2016)
  • Author(s): 武市拓也、滝 奉樹、秋山真志、杉浦一充、須賀 康
  • Organizer: 第30回表皮細胞研究会
  • Place of Presentation: アートホテル弘前シティ（青森県弘前市）
  • Year and Date: 2016-11-12
• [Presentation] 慢性湿疹を合併したALOXE3遺伝子の新規変異による先天性魚鱗癬様紅皮症の一例 (2016)
  • Author(s): 宮川祐実、武市拓也、齋藤稚代、森田明理、河野通浩、杉浦一充、秋山真志
  • Organizer: 第67回日本皮膚科学会中部支部学術大会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2016-10-22
• [Presentation] 乾癬との鑑別を要した、CARD14遺伝子変異／variantを有する毛孔性紅色粃糠疹の一例 (2016)
  • Author(s): 武市拓也、須賀 康、杉浦一充、秋山真志
  • Organizer: 第31回日本乾癬学会学術大会
  • Place of Presentation: ホテル東日本宇都宮（栃木県宇都宮市）
  • Year and Date: 2016-09-02