Disease gene identification of a new type of Ehlers-Danlos syndrome

• Project/Area Number: 21790341
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Human genetics
• Research Institution: Yokohama City University
• Principal Investigator: MIYAKE Noriko Yokohama City University, 医学部, 准教授 (40523494)
• Co-Investigator(Renkei-kenkyūsha): MATSUMOTO Naomichi 横浜市立大学, 医学研究科, 教授 (80325638) ; KOSHO Tomoki 信州大学, 医学部, 講師 (90276311)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2009: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 分子遺伝学 / 単一遺伝子疾患 / エーラス・ダンロス症候群 / 連鎖解析 / 先天性結合織疾患 / 変異解析 / 皮膚

Research Abstract

We identified CHST14 as a disease gene for the novel autosomal recessive Ehlers-Danlos syndrome (EDS). CHST14 encodes dermatan 4-O-sulfotransferase 1 (D4ST1), which transfers active sulfate to dermatan. In the mutants observed in the patients, its enzyme activity was almost completely lost and dermatan sulfate of decorin proteoglycan, a key regulator of collagen fibril assembly, was completely lost and replaced by chondroitin sulfate (CS) in the patients' fibroblasts. This may suggest that the replacement to inflexible CS, which intolerant to the mechanical compression, resulted in the impaired collagen bundle formation.

Research Products

• [Journal Article] SMOC1 is essential for ocular and limb development in humans and mice. (2011)
  • Author(s): Okada I, et al.
  • Journal Title: American Journal of Human Genetics Volume: 7 Pages: 30-41
  • Peer Reviewed
• [Journal Article] CANT1 mutation is also responsible for Desbuquois dysplasia, type 2 and Kim variant. (2011)
  • Author(s): Furuichi T, et al.
  • Journal Title: Journal of Medical Genetics Volume: 48 Pages: 32-37
  • Peer Reviewed
• [Journal Article] Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome. (2010)
  • Author(s): Miyake N, Kosho T, Mizumoto S, Furuichi T, Hatamochi A, Nagashima Y, Arai E, Takahashi K, Kawamura R, Wakui K, Takahashi J, Kato H, Yasui H, Ishida T, Ohashi H, Nishimura G, Shiina M, Saitsu H, Tsurusaki Y, Doi H, Fukushima Y, Ikegawa S, Yamada S, Sugahara K, Matsumoto N.
  • Journal Title: Human Mutation (8) Pages: 966-974
  • Peer Reviewed
• [Journal Article] A New Ehlers-Danlos Syndrome With Craniofacial Characteristics, Congenital Multiple Contractures, and Progressive Joint and Skin Laxity and Multisystem Fragility related Manifestations. (2010)
  • Author(s): Kosho T, Miyake N, Hatamochi A, Takahashi J, Kato H, Miyahara T, Igawa Y, Yasui H, Ishida T, Ono K, Kosuda T, Inoue A, Kohyama M, Hattori T, Ohashi H, Nishimura G, Kawamura R, Wakui K, Fukushima Y, Matsumoto N.
  • Journal Title: American Journal of Medical Genetics A (152) Pages: 1333-1346
  • Peer Reviewed
• [Journal Article] Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome. (2010)
  • Author(s): Miyake N, et al.
  • Journal Title: Human Mutation Volume: 31 Pages: 966-974
  • Peer Reviewed
• [Journal Article] CHN1 mutations are not a common cause of sporadic Duane's retraction syndrome. (2010)
  • Author(s): Miyake N, et al.
  • Journal Title: American Journal of Human Genetics A Volume: 152 Pages: 215-217
  • Peer Reviewed
• [Journal Article] A New Ehlers-Danlos Syndrome With Craniofacial Characteristics, Congenital Multiple Contractures, and Progressive Joint and Skin Laxity and Multisystem Fragilityrelated Manifestations (2010)
  • Author(s): Kosho T, Miyake N, et al.
  • Journal Title: American Journal of Human Genetics A Volume: 152 Pages: 1333-1346
  • Peer Reviewed
• [Journal Article] Zebrafish gene knockdowns imply roles for human YWHAG in infantile spasms and cardiomegaly. (2010)
  • Author(s): Komoike Y, et al.
  • Journal Title: Genesis Volume: 48 Pages: 233-243
  • Peer Reviewed
• [Journal Article] De novo deletion of 1q24.3-q31.2 in a patient with severe growth retardation. (2010)
  • Author(s): Nishimura A, et al.
  • Journal Title: American Journal of Medical Genetics A Volume: 152 Pages: 1322-1325
  • Peer Reviewed
• [Journal Article] Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay. (2010)
  • Author(s): Saitsu H, et al.
  • Journal Title: American Journal of Human Genetics Volume: 86 Pages: 881-891
  • Peer Reviewed
• [Journal Article] STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern. (2010)
  • Author(s): Saitsu H, et al.
  • Journal Title: Epilepsia Volume: 51 Pages: 2397-2405
  • Peer Reviewed
• [Journal Article] A novel homozygous mutation of DARS2 may cause a severe LBSL variant. (2010)
  • Author(s): Miyake N, et al.
  • Journal Title: Clinical Genetics Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Two novel CHN1 mutations in two families with Duane's retraction syndrome. (2010)
  • Author(s): Chan WM, et al.
  • Journal Title: Archives of Ophthalmology Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Paternal mosaicism of an STXBP1 mutation in OS. (2010)
  • Author(s): Saitsu H, et al.
  • Journal Title: Clinical Genetics Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] CHN1 mutations are not a common cause of sporadic Duane's retraction syndrome. (2010)
  • Author(s): Miyake N, Andrews C, Fan W, He W, Chan WM, Engle EC.
  • Journal Title: American Journal of Human Genetics A 152 Pages: 215-217
  • Peer Reviewed
• [Journal Article] Zebrafish gene knockdowns imply roles for human YWHAG in infantile spasms and cardiomegaly. (2010)
  • Author(s): Komoike Y, Fujii K, Nishimura A, Hiraki Y, Hayashidani M, Shimojima K, Nishizawa T, Higashi K, Yasukawa K, Saitsu H, Miyake N, Mizuguchi T, Matsumoto N, Osawa M, Kohno Y, Higashinakagawa T, Yamamoto T.
  • Journal Title: Genesis 48(in press)
  • Peer Reviewed
• [Journal Article] A New Ehlers-Danlos syndrome with Craniofacial characteristics, congenital mltiple contractures, and progressive joint and skin laxity and multisystem fragility-related manifestations. (2010)
  • Author(s): Kosho T, Miyake N, Hatamochi A, Takahashi J, Kato H, Miyahara T, Igawa Y, Yasui H, Ishida T, Ono K, Kosuda T, Inoue A, Kohyama M, Hattori T, Ohashi H, Nishimura G, Kawanura R, Wakui K, Fuushima Y, Matsumoto N.
  • Journal Title: American Journal of Medical Genetics A (in press)
  • Peer Reviewed
• [Journal Article] Characterization of the complex 7q21.3 rearrangement in a patient with bilateral split-foot malformation and hearing loss. (2009)
  • Author(s): Saitsu H, Kurosawa K, Kawara H, Eguchi M, Mizuguchi T, Harada N, Kaname T, Kano H, Miyake N, Toda T, Matsumoto N.
  • Journal Title: American Journal of Human Genetics A 149 Pages: 1224-1230
  • Peer Reviewed
• [Journal Article] Genetic screening of 104 patients with congenitally malformed hearts revealed a fresh mutation of GATA4 in those with atrial septal defects. (2009)
  • Author(s): Hamanoue H, Rahayuningsih SE, Hirahara Y, Itoh J, Yokoyana U, Mizuguchi T, Saitsu H, Miyake N, Hirahara F, Matsumoto N.
  • Journal Title: Cardiology in the young 13 Pages: 1-4
  • Peer Reviewed
• [Journal Article] Molecular karyotyping in 17 patients and mutation screening in 41 patients with Kabuki syudrome. (2009)
  • Author(s): Kuniba H, Yoshiura K, Kondoh T, Ohashi H, Kurosawa K, Tonoki H, Nagai T, Okamoto N, Kato M, Fukushima Y, Kaname T, Naritomi K, Matsumoto T, Moriuchi H, Kishino T, Kinoshita A, Miyake N, Matsumoto N, Niikawa N.
  • Journal Title: Journal of Human Genetics 54 Pages: 304-309
  • Peer Reviewed
• [Journal Article] A locus for ophthalmo-acromelic syndrome mapped to 10p11.23. (2009)
  • Author(s): Hamanoue H, Megarbane A, Tohma T, Nishimura A, Mizuguchi T, Saitsu H, Sakai H, Miura S, Toda T, Miyake N, Niikawa N, Yoshiura K, Hirahara F, Matsumoto N.
  • Journal Title: American Journal of Human Genetics A 149 Pages: 336-342
  • Peer Reviewed
• [Journal Article] Delineation of Dermatan 4-O-sulfotransferase 1 Deficient Ehlers-Danlos Syndrome : Observation of Two Additional Patients and Comprehensive Review of 20 Reported Patients.
  • Author(s): Shimizu K, Okamoto N, Miyake N, Taira K, Sato Y, Matsuda K, Akimaru N, Ohashi H, Wakui K, Fukushima Y, Matsumoto N, Kosho T.
  • Journal Title: American Journal of Medical Genetics A (in press)
  • Peer Reviewed
• [Presentation] Loss-of-function mutations of CHST14 cause a new type of autosomal recessive Ehlers-Danlos syndrome. (2010)
  • Author(s): Miyake N, Kosho T, Mizumoto S, Furuichi T, Hatamochi A, Ikegawa S, Yamada S, Sugahara K, Matsumoto N.
  • Organizer: American Society of Human Genetics (oral presentation)
  • Place of Presentation: アメリカ・ワシントンDC
  • Year and Date: 2010-11-03
• [Presentation] Loss-of-function mutations of CHST14 cause a new type of autosomal recessive Ehlers-Danlos syndrome (2010)
  • Author(s): Miyake N, et al.
  • Organizer: American Society of Human Genetics
  • Place of Presentation: アメリカ・ワシントンDC
  • Year and Date: 2010-11-03
• [Presentation] Carbohydrate sulfotrans-ferase 14 abnormality in human. (2010)
  • Author(s): Miyake N.
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 埼玉県大宮市(招待講演)
  • Year and Date: 2010-10-28
• [Presentation] Carbohydrate sulfotransferasc 14 abnormality in human (2010)
  • Author(s): Noriko Miyake
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 埼玉県大宮市・大宮ソニックシティーホール(招待講演)
  • Year and Date: 2010-10-28
• [Presentation] Anaysis of copy number changes in Aicardi syndrome (2009)
  • Author(s): Miyake N, Kato M, Saitsu H, Mizuguchi T, Matsumoto N
  • Organizer: The American Society of Human Genetics 59^<th> Annual Meeting
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2009-10-22
• [Presentation] メンデル遺伝性疾患の原因解明をめざして(奨励賞受講演) (2009)
  • Author(s): 三宅紀子
  • Organizer: 第54回日本人類遺伝学会
  • Place of Presentation: グランドプリンスホテル高輪
  • Year and Date: 2009-09-25
• [Presentation] Aicardi症候群における微細胞染色体異常の検索 (2009)
  • Author(s): 三宅紀子、加藤光広、才津浩智、水口剛、松本直通
  • Organizer: 第54回日本人類遺伝学会
  • Place of Presentation: グランドプリンスホテル高輪
  • Year and Date: 2009-09-24
• [Presentation] Aicardi症候群の疾患責任遺伝子の単離研究 (2009)
  • Author(s): 三宅紀子、加藤光広、才津浩智、水口剛、松本直通
  • Organizer: 第16回日本遺伝子診療学会
  • Place of Presentation: ホテル札幌ガーデンパレス
  • Year and Date: 2009-08-01
• [Patent(Industrial Property Rights)] エーラス・ダンロス症候群患者又は保因者の検出方法 (2009)
  • Inventor(s): 松本直通、三宅紀子
  • Industrial Property Rights Holder: 公立大学法人 横浜市立大学
  • Industrial Property Number: 2009-219304
  • Filing Date: 2009-09-24
• [Patent(Industrial Property Rights)] エーラス・ダンロス症候群患者又は保因者の検出方法 (2009)
  • Inventor(s): 松本直通, 三宅紀子
  • Industrial Property Rights Holder: 横浜市立大学
  • Filing Date: 2009-09-24