Cell culture model elucidates severe phenotype of female in X-linked disorder

• Project/Area Number: 15K08287
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Fujita Health University
• Principal Investigator: INAGAKI Hidehito 藤田保健衛生大学, 総合医科学研究所, 講師 (70308849)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: X連鎖 / X不活化 / ephrin / 細胞移動 / migration / モザイク

Outline of Final Research Achievements

In Mendelian disorders, X-linked diseases often manifest more severe phenotypes in men than in women. But in craniofrontonasal dysplasia women develop more severe symptoms than men do, so to say a paradox in X-linked diseases. This peculiar phenomenon is believed to be caused by random X inactivation in women, which leads to the mosaicism of normal ligand EFNB1 protein-expressing cells and mutant protein cells that disrupting normal development of embryo. In this research, I established EFNB1-expressing cell lines and observed more severe inhibition of proper cell migration under the mixture of normal cells and mutant cells, which reproduced the more severe phenotype in women in craniofrontonasal dysplasia.

Research Products

• [Journal Article] Genomic Characterization of Chromosomal Insertions: Insights into the Mechanisms Underlying Chromothripsis (2017)
  • Author(s): Kato Takema、Ouchi Yuya、Inagaki Hidehito、Makita Yoshio、Mizuno Seiji、Kajita Mitsuharu、Ikeda Toshiro、Takeuchi Kazuhiro、Kurahashi Hiroki
  • Journal Title: Cytogenetic and Genome Research Volume: 153 Issue: 1 Pages: 1-9
  • DOI: 10.1159/000481586
  • Peer Reviewed / Open Access
• [Journal Article] Intragenic DOK7 deletion detected by whole-genome sequencing in congenital myasthenic syndromes. (2017)
  • Author(s): Azuma Y, Topf A, Evangelista T, Lorenzoni PJ, Roos A, Viana P, Inagaki H, Kurahashi H, Lochmuller H
  • Journal Title: Neurol Genet Volume: 3 Issue: 3
  • DOI: 10.1212/nxg.0000000000000152
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A case with concurrent duplication, triplication, and uniparental isodisomy at 1q42.12-qter supporting microhomology-mediated break-induced replication model for replicative rearrangements (2017)
  • Author(s): Kohmoto T, Okamoto N, Naruto T, Murata C, Ouchi Y, Fujita N, Inagaki H, Satomura S, Okamoto N, Saito M, Masuda K, Kurahashi H, Imoto I
  • Journal Title: Mol Cytogenet Volume: 10 Issue: 1 Pages: 15-15
  • DOI: 10.1186/s13039-017-0316-6
  • NAID: 120006937633
  • Peer Reviewed / Open Access
• [Journal Article] Novel missense mutation in DLL4 in a Japanese sporadic case of Adams-Oliver syndrome. (2017)
  • Author(s): Taniguchi-Ikeda M, Nagasaka M, Inagaki H, Ouchi Y, Kurokawa D, Yamana K, Harada R, Nozu K, Sakai Y, Mishra SK, Yamaguchi Y, Morikoka I, Toda T, Kurahashi H, Iijima K.
  • Journal Title: Journal of Human Genetics Volume: 未定 Issue: 9 Pages: 851-855
  • DOI: 10.1038/jhg.2017.48
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A Family With Craniofrontonasal Syndrome: The First Report of Familial Cases of Craniofrontonasal Syndrome With Bilateral Cleft Lip and Palate. (2017)
  • Author(s): Inoue Y, Sakamoto Y, Sugimoto M, Inagaki H, Boda H, Miyata M, Kato H, Kurahashi H, *Okumoto T.
  • Journal Title: Cleft Palate Craniofac J Volume: 印刷中 Issue: 7 Pages: 15347-15347
  • DOI: 10.1597/15-347
  • Peer Reviewed
• [Journal Article] Palindrome-mediated translocations in humans: a new mechanistic model for gross chromosomal rearrangements. (2016)
  • Author(s): Inagaki H, Kato T, Tsutsumi M, Ouchi Y, Ohye T, *Kurahashi H.
  • Journal Title: Front Genet Volume: 7 Pages: 125-125
  • DOI: 10.3389/fgene.2016.00125
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A PDE3A mutation in familial hypertension and brachydactyly syndrome (2016)
  • Author(s): Boda H, Uchida H, Takaiso N, Ouchi Y, Fujita N, Kuno A, Hata T, et al.
  • Journal Title: J Hum Gene Volume: Apr 7 Issue: 8 Pages: 1-6
  • DOI: 10.1038/jhg.2016.32
  • NAID: 40020923782
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A simple cytogenetic method to detect chromosomally integrated human herpesvirus-6. (2016)
  • Author(s): Ohye T, et al.
  • Journal Title: J Virol Methods Volume: 228 Pages: 74-78
  • DOI: 10.1016/j.jviromet.2015.11.001
  • Peer Reviewed / Open Access
• [Journal Article] A unique TBX5 microdeletion with microinsertion detected in patient with Holt-Oram syndrome. (2015)
  • Author(s): Morine M, et al.
  • Journal Title: Am J Med Genet A Volume: 167 Issue: 12 Pages: 3192-3196
  • DOI: 10.1002/ajmg.a.37359
  • Peer Reviewed
• [Journal Article] Intragenic duplication in the PKHD1 gene in autosomal recessive polycystic kidney disease. (2015)
  • Author(s): Miyazaki J, et al.
  • Journal Title: BMC Med Genet Volume: 16 Issue: 1 Pages: 98-98
  • DOI: 10.1186/s12881-015-0245-3
  • Peer Reviewed / Open Access
• [Journal Article] PCSK5 mutation in a patient with the VACTERL association (2015)
  • Author(s): Nakamura Y. et al.
  • Journal Title: BMC Res Notes Volume: 8 Issue: 1 Pages: 228-228
  • DOI: 10.1186/s13104-015-1166-0
  • Peer Reviewed / Open Access
• [Presentation] 細胞培養モデルが明らかにしたX連鎖の疾患での女性重症化 (2017)
  • Author(s): Hidehito Inagaki
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] Cell culture model for X-linked disorder: craniofrontonasal dysplasia and severe phenotype in female (2016)
  • Author(s): Sugimoto M, Inagaki H, Tsutsumi M et al
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: Kyoto International Conferece Center (京都府京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] A PDE3A mutation in familial hypertension and brachydactyly syndrome (2016)
  • Author(s): Inagaki H, Boda H, Uchida H et al
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: Kyoto International Conferece Center (京都府京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] NGS analysis of DNA secondary structure dynamics at the promoter region (2015)
  • Author(s): 稲垣秀人他
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] Massive parallel sequencing revealed the conformational dynamics of the non-B form DNA at the promoter (2015)
  • Author(s): Inagaki H, et al.
  • Organizer: ASHG2015
  • Place of Presentation: アメリカボルティモア
  • Year and Date: 2015-10-06
  • Int'l Joint Research
• [Remarks] http://www.fujita-hu.ac.jp/~genome/mg/
• [Remarks] 分子遺伝学研究部門
  • URL: http://www.fujita-hu.ac.jp/~genome/mg/
• [Remarks] 藤田保健衛生大学総合医科学研究所
  • URL: http://www.fujita-hu.ac.jp/ICMS/