効率的大量並行シークエンスによる難治性疾患責任遺伝子同定と疾病病態の解明

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25293235
• Research Institution: Yokohama City University
• Principal Investigator: 三宅 紀子 横浜市立大学, 医学部, 准教授 (40523494)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 次世代シークエンサー / ステロイド抵抗性ネフローゼ症候群 / 肺リンパ脈管筋腫症 / NUP107 / 体細胞変異 / 全ゲノムシークエンス / ターゲットシークエンス

Outline of Annual Research Achievements

本年度までにAicardi症候群　48症例、Galloway-Mowat 症候群　24家系、ステロイド抵抗性ネフローゼ症候群　34家系、肺リンパ脈管筋腫症　24症例を集積した。各疾患の罹患者対し全エクソーム解析を行い、想定される遺伝形式従って候補となるバリアントをリスト化し、2症例以上に共通して変異のある遺伝子に着目して順次Sanger法による確認と、家系内segregationを検証した。Aicardi症候群に関しては、新規疾患遺伝子の同定には至っていないが、2症例において類似の表現型を示す別の神経疾患の既知遺伝子に病的変異を認め、臨床症状からもそれらが病因となっていると結論した。Galloway-Mowat 症候群に関しては、2家系の連鎖解析で同定された候補領域内のタンパク質翻訳領域を、全ゲノム解析で解析し、一家系において新規疾患遺伝子候補を同定しており、現在機能解析および類似症例の集積を継続している。ステロイド抵抗性ネフローゼ症候群においては、解析家系中5家系において新規疾患遺伝子NUP107を同定した。NUP107にコードされるNUP107タンパク質は核膜孔複合体の構成因子であり、糸球体濾過機能に重要な糸球体上皮細胞を含め全身に発現していること、in vitroの実験で、患者に認められたNUP107変異体では、既知の結合タンパク質であるNUP133との結合が障害されており、核膜孔への局在も障害されることを明らかにした。また、ゼブラフィッシュを用いた解析で、NUP107をノックダウンすると、糸球体の低形成、糸球体上皮細胞等、ヒトの腎病変で観察される構造異常を再現でき、本遺伝子が原因遺伝子あることを証明した (Miyake et al. Am J Hum Genet, 2015)。肺リンパ脈管筋腫症に関しては、孤発性症例に関してTSC1, TSC2遺伝子のtargeted ultra-deep sequenceを行い、9症例中6症例に体細胞モザイク変異を同定することに成功した (Fujita et al., Hum Genet, 2016)。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Causes of Carryover

27年度が最終年度であるため、記入しない。

Expenditure Plan for Carryover Budget

27年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Medical Genetics Center of Genome/Tarbiat Modares University/Isfahan University of Medical Sciences(イラン)
  • Country Name: IRAN
  • Counterpart Institution: Medical Genetics Center of Genome/Tarbiat Modares University/Isfahan University of Medical Sciences
• [Int'l Joint Research] National Research Centre/Cairo University(エジプト)
  • Country Name: EGYPT
  • Counterpart Institution: National Research Centre/Cairo University
• [Int'l Joint Research] Austin Health/Murdoch Children's Research Institute/Royal Children's Hospital(オーストラリア)
  • Country Name: AUSTRALIA
  • Counterpart Institution: Austin Health/Murdoch Children's Research Institute/Royal Children's Hospital
• [Int'l Joint Research] Seoul National Universitｙ(韓国)
  • Country Name: KOREA (REP. OF KOREA)
  • Counterpart Institution: Seoul National Universitｙ
• [Int'l Joint Research] Tel Aviv University/Hadassah-Hebrew University(イスラエル)
  • Country Name: ISRAEL
  • Counterpart Institution: Tel Aviv University/Hadassah-Hebrew University
• [Int'l Joint Research]
  • # of Other Countries: 3
• [Journal Article] Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations. (2016)
  • Author(s): Wang Z, Iida A, Miyake N, Nishiguchi KM, Fujita K, Nakazawa T, Alswaid A, Albalwi MA, Kim OH, Cho TJ, Lim GY, Isidor B, David A, Rustad CF, Merckoll E, Westvik J, Stattin EL, Grigelioniene G, Kou I, Nakajima M, Ohashi H, Smithson S, Matsumoto N, Nishimura G, Ikegawa S.
  • Journal Title: PLoS One. Volume: 11 Pages: e0150555.
  • DOI: 10.1371/journal.pone.0150555.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FDG-PET study of patients with Leigh syndrome. (2016)
  • Author(s): Haginoya K, Kaneta T, Togashi N, Hino-Fukuyo N, Kobayashi T, Uematsu M, Kitamura T, Inui T, Okubo Y, Takezawa Y, Anzai M, Endo W, Miyake N, Saitsu H, Matsumoto N, Kure S.
  • Journal Title: J Neurol Sci. Volume: 362 Pages: 309-313
  • DOI: 10.1016/j.jns.2016.02.008.
  • Peer Reviewed / Open Access
• [Journal Article] De novo GABRA1 mutations in Ohtahara and West syndromes. (2016)
  • Author(s): Kodera H, Ohba C, Kato M, Maeda T, Araki K, Tajima D, Matsuo M, Hino-Fukuyo N, Kohashi K, Ishiyama A, Takeshita S, Motoi H, Kitamura T, Kikuchi A, Tsurusaki Y, Nakashima M, Miyake N, Sasaki M, Kure S, Haginoya K, Saitsu H, Matsumoto N.
  • Journal Title: Epilepsia. Volume: 57 Pages: 566-573
  • DOI: 10.1111/epi.13344.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] De novo DNM1 mutations in two cases of epileptic encephalopathy. (2016)
  • Author(s): Nakashima M, Kouga T, Lourenço CM, Shiina M, Goto T, Tsurusaki Y, Miyatake S, Miyake N, Saitsu H, Ogata K, Osaka H, Matsumoto N.
  • Journal Title: Epilepsia. Volume: 57 Pages: e18-23.
  • DOI: 10.1111/epi.13257.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dual genetic diagnoses: Atypical hand-foot-genital syndrome and developmental delay due to de novo mutations in HOXA13 and NRXN1. (2016)
  • Author(s): Wallis M, Tsurusaki Y, Burgess T, Borzi P, Matsumoto N, Miyake N, True D, Patel C.
  • Journal Title: Am J Med Genet A. Volume: 170 Pages: 717-724
  • DOI: 10.1002/ajmg.a.37478.
  • Peer Reviewed / Open Access
• [Journal Article] Detection of low-prevalence somatic TSC2 mutations in sporadic pulmonary lymphangioleiomyomatosis tissues by deep sequencing. (2016)
  • Author(s): Fujita A, Ando K, Kobayashi E, Mitani K, Okudera K, Nakashima M, Miyatake S, Tsurusaki Y, Saitsu H, Seyama K, Miyake N, Matsumoto N.
  • Journal Title: Hum Genet. Volume: 135 Pages: 61-68
  • DOI: 10.1007/s00439-015-1611-0.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A novel homozygous mutation in HSF4 causing autosomal recessive congenital cataract. (2016)
  • Author(s): Behnam M, Imagawa E, Chaleshtori AR, Ronasian F, Salehi M, Miyake N, Matsumoto N.
  • Journal Title: J Hum Genet. Volume: 61 Pages: 177-179
  • DOI: 10.1038/jhg.2015.127.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Novel DDR2 mutation identified by whole exome sequencing in a Moroccan patient with spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type. (2016)
  • Author(s): Mansouri M, Kayserili H, Elalaoui SC, Nishimura G, Iida A, Lyahyai J, Miyake N, Matsumoto N, Sefiani A, Ikegawa S.
  • Journal Title: Am J Med Genet A. Volume: 170 Pages: 460-465
  • DOI: 10.1002/ajmg.a.37426.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Homozygous p.V116* mutation in C12orf65 results in Leigh syndrome. (2016)
  • Author(s): Imagawa E, Fattal-Valevski A, Eyal O, Miyatake S, Saada A, Nakashima M, Tsurusaki Y, Saitsu H, Miyake N, Matsumoto N.
  • Journal Title: J Neurol Neurosurg Psychiatry. Volume: 87 Pages: 212-216
  • DOI: 10.1136/jnnp-2014-310084.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay. (2016)
  • Author(s): Saitsu H, Fukai R, Ben-Zeev B, Sakai Y, Mimaki M, Okamoto N, Suzuki Y, Monden Y, Saito H, Tziperman B, Torio M, Akamine S, Takahashi N, Osaka H, Yamagata T, Nakamura K, Tsurusaki Y, Nakashima M, Miyake N, Shiina M, Ogata K, Matsumoto N.
  • Journal Title: Eur J Hum Genet. 2 Volume: 24 Pages: 129-134
  • DOI: 10.1038/ejhg.2015.92.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations. (2016)
  • Author(s): Miyake N, Tsurusaki Y, Koshimizu E, Okamoto N, Kosho T, Brown NJ, Tan TY, Yap PJ, Suzumura H, Tanaka T, Nagai T, Nakashima M, Saitsu H, Niikawa N, Matsumoto N.
  • Journal Title: Clin Genet. Volume: 89 Pages: 115-119
  • DOI: 10.1111/cge.12586.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Identification of HOXD4 Mutations in Spinal Extradural Arachnoid Cyst. (2015)
  • Author(s): Ogura Y, Miyake N, Kou I, Iida A, Nakajima M, Takeda K, Fujibayashi S, Shiina M, Okada E, Toyama Y, Iwanami A, Ishii K, Ogata K, Asahara H, Matsumoto N, Nakamura M, Matsumoto M, Ikegawa S.
  • Journal Title: PLoS One. Volume: 10 Pages: e0142126.
  • DOI: 10.1371/journal.pone.0142126.
  • Peer Reviewed / Open Access
• [Journal Article] De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing. (2015)
  • Author(s): Saitsu H, Akita T, Tohyama J, Goldberg-Stern H, Kobayashi Y, Cohen R, Kato M, Ohba C, Miyatake S, Tsurusaki Y, Nakashima M, Miyake N, Fukuda A, Matsumoto N.
  • Journal Title: Sci Rep. Volume: 5 Pages: 15199
  • DOI: 10.1038/srep15199.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome. (2015)
  • Author(s): Miyake N, Tsukaguchi H, Koshimizu E, Shono A, Matsunaga S, Shiina M, Mimura Y, Imamura S, Hirose T, Okudela K, Nozu K, Akioka Y, Hattori M, Yoshikawa N, Kitamura A, Cheong HI, Kagami S, Yamashita M, Fujita A, Miyatake S, Tsurusaki Y, Nakashima M, Saitsu H, Ohashi K, Imamoto N, Ryo A, Ogata K, Iijima K, Matsumoto N.
  • Journal Title: Am J Hum Genet. Volume: 97 Pages: 555-566
  • DOI: 10.1016/j.ajhg.2015.08.013.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance. (2015)
  • Author(s): Ohba C, Haginoya K, Osaka H, Kubota K, Ishiyama A, Hiraide T, Komaki H, Sasaki M, Miyatake S, Nakashima M, Tsurusaki Y, Miyake N, Tanaka F, Saitsu H, Matsumoto N.
  • Journal Title: J Hum Genet. Volume: 60 Pages: 739-742
  • DOI: 10.1038/jhg.2015.108.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Denovo KCNT1 mutations in early-onset epileptic encephalopathy. (2015)
  • Author(s): Ohba C, Kato M, Takahashi N, Osaka H, Shiihara T, Tohyama J, Nabatame S, Azuma J, Fujii Y, Hara M, Tsurusawa R, Inoue T, Ogata R, Watanabe Y, Togashi N, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Tanaka F, Saitsu H, Matsumoto N.
  • Journal Title: Epilepsia Volume: 56 Pages: e121-128
  • DOI: 10.1111/epi.13072.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Novel compound heterozygous LIAS mutations cause glycine encephalopathy. (2015)
  • Author(s): Tsurusaki Y, Tanaka R, Shimada S, Shimojima K, Shiina M, Nakashima M, Saitsu H, Miyake N, Ogata K, Yamamoto T, Matsumoto N.
  • Journal Title: J Hum Genet. Volume: 60 Pages: 631-635
  • DOI: 10.1038/jhg.2015.72.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] De Novo 17q24.2-q24.3 microdeletion presenting with generalized hypertrichosis terminalis, gingival fibromatous hyperplasia, and distinctive facial features. (2015)
  • Author(s): Afifi HH, Fukai R, Miyake N, Gamal El Din AA, Eid MM, Eid OM, Thomas MM, El-Badry TH, Tosson AM, Abdel-Salam GM, Matsumoto N.
  • Journal Title: Am J Med Genet A. Volume: 167A Pages: 2418-2424.
  • DOI: 10.1002/ajmg.a.37185.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb. (2015)
  • Author(s): Nakashima M, Saitsu H, Takei N, Tohyama J, Kato M, Kitaura H, Shiina M, Shirozu H, Masuda H, Watanabe K, Ohba C, Tsurusaki Y, Miyake N, Zheng Y, Sato T, Takebayashi H, Ogata K, Kameyama S, Kakita A, Matsumoto N.
  • Journal Title: Ann Neurol. Volume: 78 Pages: 375-386
  • DOI: 10.1002/ana.24444.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Short-lasting unilateral neuralgiform headache attacks with ispilateral facial flushing is a new variant of paroxysmal extreme pain disorder. (2015)
  • Author(s): Imai N, Miyake N, Saito Y, Kobayashi E, Ikawa M, Manaka S, Shiina M, Ogata K, Matsumoto N.
  • Journal Title: J Headache Pain. Volume: 16 Pages: 519
  • DOI: J Headache Pain.
  • Peer Reviewed / Open Access
• [Journal Article] Biotin-responsive basal ganglia disease: a case diagnosed by whole exome sequencing. (2015)
  • Author(s): Kohrogi K, Imagawa E, Muto Y, Hirai K, Migita M, Mitsubuchi H, Miyake N, Matsumoto N, Nakamura K, Endo F.
  • Journal Title: Biotin-responsive basal ganglia disease: a case diagnosed by whole exome sequencing. Volume: 60 Pages: 381-385
  • DOI: 10.1038/jhg.2015.35.
  • Peer Reviewed / Open Access
• [Journal Article] Japanese familial case of myoclonus-dystonia syndrome with a splicing mutation in SGCE. (2015)
  • Author(s): Wada T, Takano K, Tsurusaki Y, Miyake N, Nakashima M, Saitsu H, Matsumoto N, Osaka H.
  • Journal Title: Pediatr Int. Volume: 57 Pages: 324-326.
  • DOI: 10.1111/ped.12613.
  • Peer Reviewed / Open Access
• [Journal Article] GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders. (2015)
  • Author(s): Ohba C, Shiina M, Tohyama J, Haginoya K, Lerman-Sagie T, Okamoto N, Blumkin L, Lev D, Mukaida S, Nozaki F, Uematsu M, Onuma A, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Tanaka F, Kato M, Ogata K, Saitsu H, Matsumoto N.
  • Journal Title: Epilepsia. Volume: 56 Pages: 841-848
  • DOI: 10.1111/epi.12987.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A family of distal arthrogryposis type 5 due to a novel PIEZO2 mutation. (2015)
  • Author(s): Okubo M, Fujita A, Saito Y, Komaki H, Ishiyama A, Takeshita E, Kojima E, Koichihara R, Saito T, Nakagawa E, Sugai K, Yamazaki H, Kusaka K, Tanaka H, Miyake N, Matsumoto N, Sasaki M.
  • Journal Title: Am J Med Genet A. Volume: 167A Pages: 1100-1106
  • DOI: 10.1002/ajmg.a.36881.
  • Peer Reviewed / Open Access
• [Journal Article] A case of autism spectrum disorder arising from a de novo missense mutation in POGZ. (2015)
  • Author(s): Fukai R, Hiraki Y, Yofune H, Tsurusaki Y, Nakashima M, Saitsu H, Tanaka F, Miyake N, Matsumoto N.
  • Journal Title: J Hum Genet. Volume: 60 Pages: 277-279
  • DOI: 10.1038/jhg.2015.13.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Japanese case of cerebellar ataxia, spastic paraparesis and deep sensory impairment associated with a novel homozygous TTC19 mutation. (2015)
  • Author(s): Kunii M, Doi H, Higashiyama Y, Kugimoto C, Ueda N, Hirata J, Tomita-Katsumoto A, Kashikura-Kojima M, Kubota S, Taniguchi M, Murayama K, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Matsumoto N, Tanaka F.
  • Journal Title: J Hum Genet. Volume: 60 Pages: 187-191
  • DOI: 10.1038/jhg.2015.7.
  • Peer Reviewed / Open Access
• [Journal Article] Detecting copy-number variations in whole-exome sequencing data using the eXome Hidden Markov Model: an 'exome-first' approach. (2015)
  • Author(s): Miyatake S, Koshimizu E, Fujita A, Fukai R, Imagawa E, Ohba C, Kuki I, Nukui M, Araki A, Makita Y, Ogata T, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Matsumoto N.
  • Journal Title: J Hum Genet. Volume: 60 Pages: 175-182
  • DOI: 10.1038/jhg.2014.124.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Two novel homozygous RAB3GAP1 mutations cause Warburg micro syndrome. (2015)
  • Author(s): Imagawa E, Fukai R, Behnam M, Goyal M, Nouri N, Nakashima M, Tsurusaki Y, Saitsu H, Salehi M, Kapoor S, Tanaka F, Miyake N, Matsumoto N.
  • Journal Title: Hum Genome Var. Volume: 2 Pages: 15034
  • DOI: 10.1038/hgv.2015.34.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Wiedemann-Steiner症候群における新規KMT2A変異と臨床症状の検討 (2015)
  • Author(s): 三宅紀子, 鶴﨑美徳, 輿水江里子,新川詔夫, 松本直通
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル、東京
  • Year and Date: 2015-10-14 – 2015-10-17
• [Presentation] Clinical and genetic analysis of Wiedemann Steiner syndrome caused by KMT2A mutations (2015)
  • Author(s): Noriko Miyake, Yoshinori Tsurusaki, Eriko Koshimizu, Norio Niikawa, Naomichi Matsumoto
  • Organizer: American Society of Human Genetics 65th Annual Meeting
  • Place of Presentation: Baltimore Convention Center, Baltimore, MD, USA
  • Year and Date: 2015-10-06 – 2015-10-10
  • Int'l Joint Research
• [Presentation] Clinical and genetic analysis of Wiedemann Steiner syndrome caused by KMT2A mutations (2015)
  • Author(s): Noriko Miyake, Yoshinori Tsurusaki, Eriko Koshimizu, Nobuhiko Okamoto, Tomoki Kosho, Natasha Jane Brown, Tiong Yang Tan, Patrick Jia Jiunn Yap, Hiroshi Suzumura, Toju Tanaka, Toshiro Nagai, Norio Niikawa, Naomichi Matsumoto
  • Organizer: The 11th International Workshop on Advanced Genomics
  • Place of Presentation: 一橋大学 一橋講堂 、東京
  • Year and Date: 2015-05-20 – 2015-05-22
  • Int'l Joint Research