ヒト脳神経疾患を惹起するシナプス関連分子異常探索

• Project Area: Generation of synapse-neurocircuit pathology
• Project/Area Number: 23110513
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Yokohama City University
• Principal Investigator: 松本 直通 横浜市立大学, 医学研究科, 教授 (80325638)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000); Fiscal Year 2012: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2011: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: シナプス関連分子 / 遺伝子変異 / 次世代シーケンス / てんかん / 脊髄小脳変性症

Research Abstract

KCNQ2は電位依存性カリウムチャネルのKv7.2サブユニットをコードしており、その変異が予後良好の良性家族性新生児痙攣(benign familial neonatal convulsion : BFNS)を引き起こすことが知られていた。しかし、2012年に入り、最重症の難治性のてんかんである太田原症候群(Ohtahara syndrome : OS)を含めた新生児てんかん性脳症を引き起こすことが明らかとなった。今回我々は、新生児期から乳児期にかけて発症したてんかん患者239例【OS51例、West症候群(WS)104例、その他のてんかん患者84例】について、KCNQ2変異のスクリーニングを行った。
Hight resolution melting法による変異スクリーニング、あるいはWhole exome sequencingにより、10種類のミスセンス変異を12症例に同定した。9症例はOSの診断であり、1症例がWS、2症例が分類不能のてんかん性脳症であった。11症例ではde novo変異であることが確認でき、1症例では新生児てんかんの既往を有する母親がmosaicで変異を有していた。初発の痙攣発作は強直痙攣がほとんどであり、12症例全てで新生児期に発作を認めた。太田原症候群の特徴である、サプレッション-バーストパターンの脳波は、類似例も含めると11症例で認めた。OSの約75%はWSに移行することが知られているが、2症例のみがWSへの移行を認めた(2/9,22%)。10症例では抗てんかん薬によってけいれんのコントロールが可能であったが、3カ月で死亡した例を除いて全例で重度の知的障害を認めた。2つのミスセンス変異(p. Ala294Val, p. Arg533Trp)がBFNSで報告のあるアミノ酸の変異であり、BFNS症例と比較してミスセンス変異の局在に明らかな差異は認めなかった。

Research Products

• [Journal Article] Whole exome sequenwcing identifies KCNQ2 mutations in Ohtahara syndrome. (2012)
  • Author(s): Saitsu H, et al, Matsumoto N.
  • Journal Title: Ann Neurol Volume: 72 Pages: 298-230
  • Peer Reviewed
• [Journal Article] De novo and inherited mutations in the gene encoding a type IV collagen α2 chain (COL4A2) cause porencephaly. (2012)
  • Author(s): Yoneda Y, et al., Matsumoto N, et al.
  • Journal Title: Am J Hum Genet Volume: 90 Pages: 86-90
  • Peer Reviewed
• [Journal Article] Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. (2012)
  • Author(s): Tsurusaki Y, et al., Matsumoto N.
  • Journal Title: Nat Genet Volume: 44 Pages: 376-378
  • Peer Reviewed
• [Journal Article] CASK aberrations in males with Ohtahara syndrome and cerebellar hypoplasia (2012)
  • Author(s): Saitsu H, et al., Matsumoto N.
  • Journal Title: Epilepsia Volume: 53 Pages: 1441-1449
  • Peer Reviewed
• [Journal Article] SMOC1 is essential for ocular and limb development in humans and mice (2011)
  • Author(s): Okada I, et al., Matsumto N, et al
  • Journal Title: Am J Hum Genet Volume: 88 Pages: 30-41
  • Peer Reviewed
• [Journal Article] Dandy-Walker malformation associated with heterozygous ZIC1 and ZIC4 deletion : Report of a new patient (2011)
  • Author(s): Tohyama J, et al., Matsumoto N
  • Journal Title: Am J Med Genet Part A Volume: 155 Pages: 130-131
  • Peer Reviewed
• [Journal Article] CANT1 is also responsible for Desbuquois dysplasia, type 2 and Kim variant (2011)
  • Author(s): Furuichi T, et al., Matsumoto N, et al
  • Journal Title: J Med Genet Volume: 48 Pages: 32-37
  • Peer Reviewed
• [Journal Article] Paternal mosaicism of a STXBP1 mutation in Ohtahara syndrome (2011)
  • Author(s): Saitsu H, et al., Matsumoto N
  • Journal Title: Clin Genet Volume: 80 Pages: 484-488
  • Peer Reviewed
• [Journal Article] Familial Simpson-Golabi-Behmel syndrome : Studies of X-chromosome inactivation and clinical phenotypes in two female individuals with GPC3 mutations (2011)
  • Author(s): Yano S, et al., Matsumoto N, et al
  • Journal Title: Clin Genet Volume: 80 Pages: 466-471
  • Peer Reviewed
• [Journal Article] Breakpoint determination of X ; autosome balanced translocations in four patients with premature ovarian failure (2011)
  • Author(s): Nishimura-Tadaki A, et al., Matsumoto N
  • Journal Title: J Hum Genet Volume: 52 Pages: 156-160
  • Peer Reviewed
• [Journal Article] A de novo deletion of 20q11.2-q12 in a boy presenting with abnormal hands and feet, retinal dysplasia, and intractable feeding difficulty (2011)
  • Author(s): Hiraki Y, et al, Matsumoto N
  • Journal Title: Am J Med Genet Part A Volume: 152 Pages: 409-414
  • Peer Reviewed
• [Journal Article] Axenfeld-Rieger anomaly and Axenfeld-Rieger syndrome : clinical, molecular-cytogenetic, and DNA array analyses on three patients with chromosomal defects at 6p25 (2011)
  • Author(s): Tonoki H, et al., Matsumoto N, et al
  • Journal Title: Am J Med Genet Part A Volume: 155 Pages: 2925-2932
  • Peer Reviewed
• [Journal Article] De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis (2011)
  • Author(s): Tadaki H, et al., Matsumoto N
  • Journal Title: J Hum Genet Volume: 56 Pages: 343-347
  • Peer Reviewed
• [Journal Article] A novel homozygous mutation of DARS2 may cause a severe LBSL variant (2011)
  • Author(s): Miyake N, et al., Matsumoto N
  • Journal Title: Clin Genet Volume: 80 Pages: 293-296
  • Peer Reviewed
• [Journal Article] Exonic deletion of CASP10 in a patient presenting with systemic juvenile idiopathic arthritis, but not with autoimmune lymphoproliferative syndrome type IIa (2011)
  • Author(s): Tadaki H, et al., Matsumoto N
  • Journal Title: Int J Immunogenet Volume: 38 Pages: 287-293
  • Peer Reviewed
• [Journal Article] Rapid detection of a mutation causing X-linked leukodystrophy by exome sequencing.j (2011)
  • Author(s): Tsurusaki Y, et al., Matsumoto N, et al
  • Journal Title: J Med Genet Volume: 48 Pages: 606-609
  • Peer Reviewed
• [Journal Article] Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) in an infant with Down syndrome (2011)
  • Author(s): Narumi Y, et al., Matsumoto N, et al
  • Journal Title: Clin Dysmorphol Volume: 20 Pages: 166-167
  • Peer Reviewed
• [Journal Article] A founder mutation of CANT1 common in Korean and Japanese Desbuquois dysplasia (2011)
  • Author(s): Dai J, et al., Matsumoto N, et al
  • Journal Title: J Hum Genet Volume: 56 Pages: 398-400
  • Peer Reviewed
• [Journal Article] Genetic commentary : De novo mutations in epilepsy (2011)
  • Author(s): Saitsu H, Matsumoto N
  • Journal Title: Dev Med Child Neurol Volume: 53 Pages: 806-807
  • 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 (2011)
  • Author(s): Shimizu K, et al., Matsumoto N, et al
  • Journal Title: Am J Med Genet Part A Volume: 155 Pages: 1949-1958
  • Peer Reviewed
• [Journal Article] Early infantile epileptic encephalopathy associated with the disrupted gene encoding Slit-Robo Rho GTPase activating protein 2 (SRGAP2) (2011)
  • Author(s): Saitsu H, et al., Matsumoto N
  • Journal Title: Am J Med Genet Part A Volume: 158 Pages: 199-205
  • Peer Reviewed
• [Journal Article] Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal recessive hypomyelinating leukoencephalopathy (2011)
  • Author(s): Saitsu H, et al., Matsumoto N
  • Journal Title: Am J Hum Genet Volume: 90 Pages: 86-90
  • Peer Reviewed
• [Journal Article] Exome sequencing of two patients in a family with atypical X-linked leukodystrophy (2011)
  • Author(s): Tsurusaki Y, et al., Matsumoto N
  • Journal Title: Clin Genet Volume: 80 Pages: 161-166
  • Peer Reviewed
• [Journal Article] Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome (2011)
  • Author(s): Hannibal MC, et al., Matsumoto N, et al
  • Journal Title: Am J Med Genet Part A Volume: 155 Pages: 1511-1516
  • Peer Reviewed
• [Journal Article] A response to : Loss of dermatan-4-sulfotransferase 1 (D4ST1/CHST14) function represents the first dermatan sulfate biosynthesis defect, "Dermatan sulfate-deficient adducted thumb-clubfoot syndrome". Which name is appropriate, "Adducted thumb-clubfoot syndrome" or "Ehlers-Danlos syndrome"? (2011)
  • Author(s): Kosho T, et al., Matsumoto N
  • Journal Title: Hum Mut Volume: 32 Pages: 1507-1509
  • Peer Reviewed
• [Journal Article] Exome sequencing reveals a homozygous SYT14 mutation in adult-onset autosomal recessive spinocerebellar ataxia with psychomotor retardation (2011)
  • Author(s): Doi H, et al., Matsumoto N
  • Journal Title: Am J Hum Genet Volume: 89 Pages: 320-327
  • Peer Reviewed
• [Journal Article] A homozygous Mutation in RNU4ATAC as a cause of microcephalic osteodysplastic primordial dwarfism type I (MOPDI) with associated pigmentary disorder (2011)
  • Author(s): Abdel-Salam GMH, et al., Matsumoto N
  • Journal Title: Am J Med Genet Part A Volume: 155 Pages: 2885-2896
  • Peer Reviewed
• [Presentation] Mendelian exome. (2012)
  • Author(s): Matsumoto N
  • Organizer: The 12^<th> annual meeting of East Asian Union of Human Genetics Societies.
  • Place of Presentation: ソウル国立大学病院・ソウル・韓国
  • Year and Date: 2012-11-29
• [Presentation] Exome sequencing in mendelian disorders. (2012)
  • Author(s): Matsumoto N
  • Organizer: Translational Genomics Conference 2012
  • Place of Presentation: ハイアットリージェンシー済州島・韓国
  • Year and Date: 2012-10-13
• [Presentation] Disease genome analysis using next generation sequencer (2011)
  • Author(s): Naomichi Matsumoto
  • Organizer: The 34^<th> annual meeting of the molecular biology society of Japan
  • Place of Presentation: Pacifico Yokohama, Yokohama(invited speaker)
  • Year and Date: 2011-12-14
• [Presentation] 遺伝性神経疾患のエクソーム解析 (2011)
  • Author(s): 松本直通
  • Organizer: 国立精神・神経医療研究センターTMC棟/クラスター研究棟開棟記念講演会
  • Place of Presentation: 国立精神・神経医療研究センター・小平(招待講演)
  • Year and Date: 2011-11-22
• [Presentation] ヒト遺伝性疾患の原因解明を目指して (2011)
  • Author(s): 松本直通
  • Organizer: 日本人類遺伝学会第56回大会
  • Place of Presentation: 幕張メッセ・千葉(学会賞受賞講演)(招待講演)
  • Year and Date: 2011-11-11
• [Presentation] 次世代シーケンサーを用いたヒト疾患ゲノム解析法 (2011)
  • Author(s): 松本直通
  • Organizer: 日本人類遺伝学会第56回大会
  • Place of Presentation: 幕張メッセ・千葉(招待講演)
  • Year and Date: 2011-11-11
• [Presentation] 次世代シーケンサーを用いた疾患ゲノム解析の現状 (2011)
  • Author(s): 松本直通
  • Organizer: 第18回遺伝性疾患に関する出生前診断研究会
  • Place of Presentation: 佐賀大学医学部・佐賀(招待講演)
  • Year and Date: 2011-10-01
• [Presentation] 次世代シーケンス法による疾患研究の最前線 (2011)
  • Author(s): 松本直通
  • Organizer: 第一回サイトジェノミクスセミナー
  • Place of Presentation: 三菱化学メディエンス志村事業所・東京(招待講演)
  • Year and Date: 2011-09-17
• [Presentation] もやもや病の遺伝学:最近わかってきたこと (2011)
  • Author(s): 松本直通
  • Organizer: 大阪難症例脳血管疾患研究会・大阪もやもや病研究会
  • Place of Presentation: 千里阪急ホテル・大阪(招待講演)
  • Year and Date: 2011-06-18
• [Remarks]
  • URL: http://www.yokohama-cu.ac.jp/amedrc/res/matsumoto2011_8.html
• [Remarks]
  • URL: http://www.yokohama-cu.ac.jp/amedrc/res/matsumoto2011_10.html
• [Remarks]
  • URL: http://www.yokohama-cu.ac.jp/amedrc/res/saitsu2011_12.html
• [Remarks]
  • URL: http://www.yokohama-cu.ac.jp/amedrc/res/matsumoto2012_03.html
• [Remarks]
  • URL: http://www.yokohama-cu.ac.jp/amedrc/res/matsumoto2012_0319.html
• [Patent(Industrial Property Rights)] コフィン-シリス症候群の検出方法 (2012)
  • Inventor(s): 松本直通・鶴崎美徳・三宅紀子
  • Industrial Property Rights Holder: 横浜市立大学
  • Industrial Property Number: 2012-000136
  • Filing Date: 2012-01-04
• [Patent(Industrial Property Rights)] 常染色体劣性遺伝性脊髄小脳変性症の検出方法 (2011)
  • Inventor(s): 松本直通・土井宏
  • Industrial Property Rights Holder: 横浜市立大学
  • Industrial Property Number: 2011-136277
  • Filing Date: 2011-06-20
• [Patent(Industrial Property Rights)] RNF213遺伝子多型による重症型もやもや病の予測方法 (2011)
  • Inventor(s): 松本直通・宮武聡子
  • Industrial Property Rights Holder: 横浜市立大学
  • Industrial Property Number: 2011-175013
  • Filing Date: 2011-08-10
• [Patent(Industrial Property Rights)] び慢性大脳白質形成不全症の検出方法 (2011)
  • Inventor(s): 才津浩智・松本直通
  • Industrial Property Rights Holder: 横浜市立大学
  • Industrial Property Number: 2011-226488
  • Filing Date: 2011-10-14
• [Patent(Industrial Property Rights)] 孔脳症および周産期脳出血の検出方法 (2011)
  • Inventor(s): 才津浩智・松本直通
  • Industrial Property Rights Holder: 横浜市立大学
  • Industrial Property Number: 2011-247457
  • Filing Date: 2011-11-11