Comprehensive genetic analysis by DNA Chip in inherited neuropathies

• Project/Area Number: 18390262
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Kagoshima University
• Principal Investigator: ARIMURA Kimiyoshi Kagoshima University, 大学院・医歯学総合研究科, Associate Professor (20159510)
• Co-Investigator(Kenkyū-buntansha): TAKASHIMA Hiroshi Kagoshima University, 大学院・医歯学総合研究科, Assistant Professor (80372803) ; SOBUE Gen Nagoya University, 大学院・医学系研究科, Professor (20148315) ; NAKAGAWA Masanori Kyoto prefectural University, 大学院・医学研究科, Professor (50198040) ; HAYASAKA Kiyoshi Yamagata University, 医学部, Professor (20142961)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥17,100,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥1,500,000); Fiscal Year 2007: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2006: ¥10,600,000 (Direct Cost: ¥10,600,000)
• Keywords: Charcot-Marie-Tooth disease / CMT / DNA chip / reseguencing method / genetic diagnosis / molecular diagnosis / inherited neuropathy / mutation screening / resequencing array / multiple PCR / 遺伝子検査

Research Abstract

Inherited neuropathies are clinically and genetically heterogeneous. At least 28 genes and 12 loci have been associated with Charcot-Marie-Tooth disease (CMT). Genotype-phenotype correlations of these genes are important for understanding the pathomechanisms of inherited neuropathy. Some clinical trials have been conducted for the treatment of CMT1A patients, and therefore, genetic diagnosis is becoming more important. However, concomitant with the increase in the number of genes to be screened for mutations, the labor and reagent costs for molecular genetic testing have also increased significantly. Direct sequence analysis is the standard method for mutation detection, but DNA sequencing costs are considerable. Therefore, sensitive, high-throughput, and cost-effective mutation screening methods are desired. Recent advances in microarray-based resequencing technology appear to provide accurate and economical mutation detection.
We developed a microarray-based resequencing system to detect sequence alterations in multiple CMT genes on a single,high-throughput platform. We designed a microarray chip that includes both strands of the target exons and the splice sites. A total of 110,938 bp of sequences obtained from 27 disease causing and 10 disease candidate genes associated with peripheral nerves were tiled on a resequencing DNA chip. A total of 586 primer sets were amplified by multiplex PCR methods, and 69 kinds of alterations in 20 disease causing genes were identified. Some of the alterations are potentially pathogenic ; however, additional analysis is needed to determine whether these changes are responsible for CMT. Quality of resequencing is equivalent of direct sequencing, suggesting that our CMT diagnostic DNA chip is a useful technology for determining sequence alterations. Our microarray resequencing system is a sensitive,cost-effective, and high-throughput screening method for mutation detection in CMT patients.

Research Products

• [Journal Article] Prevalence and incidence rates of chronic inflammatory demyelinating polyneuropathy in the Japanese population (2008)
  • Author(s): Iijima M, et. al.
  • Journal Title: J Neurol Neurosurg Psychiatry (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Familial Parkinsonism with Digenic Parkin and PINKl mutations (2008)
  • Author(s): Funayama M, et. al.
  • Journal Title: Movement Disorders (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Prevalence and incidence rates of chronic inflammatory demyelinating polyneuropathy in the Japanese population (2008)
  • Author(s): Iijima, M., Koike, H., Hattori, N., Tamakoshi, A., Katsuno, M., Tanaka, F., Yamamoto, M., Arimura, K., Sobue, G
  • Journal Title: J Neurol Neurosurg Psychiatry (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Comparative electrophysiological study of response to botulinum toxin type B in Japanese and Caucasians (2008)
  • Author(s): Arimura K, et. al.
  • Journal Title: Mov Disord. 23 Pages: 240-245
  • Peer Reviewed
• [Journal Article] Prevalence and incidence rates of chronic inflammatory demyelinating polyneuropathy in the Japanese population. (2008)
  • Author(s): Iijima M, et. al.
  • Journal Title: J Neurol Neurosurg Psychiatry (印刷中)
  • Peer Reviewed
• [Journal Article] Muscle membrane excitability after exercise in thyrotoxic periodic paralysis and thyrotosicosis without periodic paralysis (2007)
  • Author(s): Arimura K, Arimura Y, Ng AR, Sakoda S, Higuchi I.
  • Journal Title: Muscle Nerve 36 Pages: 784-788
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Spinocerebellar ataxia with axonal neuropathy:consequence of a Tdpl Tecessive neomorphic mutation (2007)
  • Author(s): Hirano R, Takashima H, et. al.
  • Journal Title: EMBO J 26 Pages: 4732-4743
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 遺伝性ニューロパチーの診断と病態 (2007)
  • Author(s): 高嶋 博
  • Journal Title: Peripheral Nerve末梢神経 18 Pages: 145-151
  • NAID: 10027267294
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy with proximal dominancy(HMSN-P)and genetic heterogeneity (2007)
  • Author(s): Maeda K, et. al.
  • Journal Title: J Hum Genet 52 Pages: 907-914
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 遺伝性ニューロパチーの進歩 (2007)
  • Author(s): 高嶋 博、有村 公良
  • Journal Title: Clinical Neuroscience 25 Pages: 752-754
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Ataxic vs painful form of paraneoplastic neuropathy (2007)
  • Author(s): Oki Y, Koike H, Iijima M, et. al.
  • Journal Title: Neurology 69 Pages: 564-572
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Intravenous inununoglobulin therapy markedly ameliorates muscle weakness and severe pain in proximal diabetic neuropathy (2007)
  • Author(s): Kawagashira Y, Watanabe H, Oki Y, et. al.
  • Journal Title: J Neurol Neurosurg Psychiatry 78 Pages: 899-901
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Nonmyelinating Schwann cell involvement with well-preserved unmyelinated axons in Charcot-Marie-Tooth disease type 1A (2007)
  • Author(s): Koike H, Iijima M, Mori K, et. al.
  • Journal Title: J Neuropathol Eap Neurol 66 Pages: 1027-1036
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 遺伝性ニューロパチーの病態と治療 (2007)
  • Author(s): 中川 正法
  • Journal Title: 末梢神経 18 Pages: 1-13
  • NAID: 10024898847
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Charcot-Marie-Tooth病1Aに対するアスコルビン酸投与の有効性の検討 (2007)
  • Author(s): 中川 正法、野寺 裕之、服部 直樹, 他
  • Journal Title: Perihperal Nerve 18 Pages: 210-212
  • NAID: 10027267461
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 神経疾患と自己抗体.抗K+チャネル(VGKC)抗体に関連する神経疾患スペクトラム (2007)
  • Author(s): 有村 公良, 渡邊 修, 長堂 竜維
  • Journal Title: 臨床神経学 47 Pages: 845-847
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Serum VEGF-as a prognostic factor of atherosclerosis (2007)
  • Author(s): Kimura K, et. al.
  • Journal Title: Atherosclerosis 194 Pages: 182-188
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Comparative electrophysiological study of response to botulinum toxin type B in Japanese and Caucasians (2007)
  • Author(s): Arimura K, et. al.
  • Journal Title: Mov Disord 23 Pages: 240-245
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Muscle membrane excitability after exercise in thyrotoxic periodic paralysis and thyrotoxicosis without periodic paralysis (2007)
  • Author(s): Arimura, K., Arimura, Y., Ng, AR., Sakoda S., Higuchi, I
  • Journal Title: Muscle Nerve 36 Pages: 784-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Spinocerebellar ataxia with axonal neuropathy : consequence of a Tdp1 recessive neomorphic mutation? (2007)
  • Author(s): Hirano, R., Interthal, H., Huang, C., Nakamura, T., Deguchi, K., Choi, K., Bhattacharjee, MB., Arimura, K., Umehara, F., Izumo, S., Northrop, JL., Salih, MA., Inoue, K., Armstrong, PL., Champoux, JJ., Takashima, H., Boerkoel, CF
  • Journal Title: EMBO J. 26 Pages: 4732-43
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy with proximal dominancy(HMSN-P) and genetic heterogeneity (2007)
  • Author(s): Maeda, K., Kaji, R., Yasuno, K., Jambaldorj, J., Nodera, H., Takashima, H., Nakaeawa, M., Makino, S., Tamiya, G
  • Journal Title: J Hum Genet 52 Pages: 907-914
  • NAID: 10019798455
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Serum VEGF as a prognostic factor of atherosclerosis (2007)
  • Author(s): Kimura, K., Hashiguchi, T., Deguchi, T., Horinouchi, S., Uto, T., Oku, H., Setoyama, S., Maruyama, I., Osame, M., Arimura, K
  • Journal Title: Atherosclerosis 194 Pages: 182-188
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Comparative electrophysiological study of response to botulinum toxin type B in Japanese and Caucasians (2007)
  • Author(s): Arimura, K., Arimura, Y., Takata, Y., Nakamura, T., Kaii, R
  • Journal Title: Mov. Disord 3 Pages: 240-245
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ataxic vs painful form of paraneoplastic neuropathy (2007)
  • Author(s): Oki, Y., Koike, H., Iijima, M., Mori, K., Hatlori, N., Katsuno, M., Nakamura, T., Hirayama, M., Tanaka, F., Shiraishi, M., Yazaki, S., Nokura, K., Yamamoto, H., Sobue, G
  • Journal Title: J Neurol Neurosurg Psychiatry 78 Pages: 899-901
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nonmyelinating Schwann cell involvement with well-preserved unmyelinated axons in Charcot-Marie-Tooth disease type 1A (2007)
  • Author(s): Koike, H., Iijima, M., Mori, K., Yamamoto, M., Hattoi-i, N., Katsuno, M., Tanaka, F., Watanabe, H., Doyu, M., Yoshikawa, H., Sobue, G
  • Journal Title: J Neuropathol Exp Neurol 66 Pages: 1027-36
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation? (2007)
  • Author(s): Hirano R, Takashima H, et. al.
  • Journal Title: EMBO J 26 Pages: 4732-4743
  • Peer Reviewed
• [Journal Article] Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) and genetic heterogeneity. (2007)
  • Author(s): Maeda K, et. al.
  • Journal Title: J Hum Genet 52 Pages: 907-914
  • Peer Reviewed
• [Journal Article] 遺伝性ニューロパチーの進歩 (2007)
  • Author(s): 高嶋 博、有村公良
  • Journal Title: Clinical Neuroscience 25(7) Pages: 752-754
• [Journal Article] 神経疾患と自己抗体.抗K+チャネル(VGKC)抗体に関連する神経疾患スペクトラム. (2007)
  • Author(s): 有村公良, 渡邊修, 長堂竜維
  • Journal Title: 臨床神経学 47 Pages: 845-847
  • Peer Reviewed
• [Journal Article] Serum VEGF-as a prognostic factor of atherosclerosis. (2007)
  • Author(s): Kimura K, et. al.
  • Journal Title: Atherosclerosis 194 Pages: 182-188
  • Peer Reviewed
• [Journal Article] 末梢神経疾患治療の進歩 (2006)
  • Author(s): 有村 公良
  • Journal Title: 神経治療学 23 Pages: 395-398
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 神経伝導検査における伝導ブロック様所見は後天性脱髄性疾患だけに特異的 (2006)
  • Author(s): 有村 由美子, 有村 公良
  • Journal Title: 臨床脳波 48 Pages: 191-194
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Charcot-Marie-Tooth病1Aに対するアスコルビン酸投与の試み (2006)
  • Author(s): 中川 正法, 石神 紀子, 近藤 正樹, 山口 達之, 吉田 誠克, 有村 公良
  • Journal Title: 末梢神経 17 Pages: 308-312
  • NAID: 10027578209
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Association of AKT1 haplotype with the risk of schizophrenia in Iranian population (2006)
  • Author(s): Bajestan SN, Sabouri AH, Nakamura M, et. al.
  • Journal Title: Am J Med Genet B Neuropsychiatr Genet 141 Pages: 383-386
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Early clinical signs and imaging Gerstmann-Straussler-Scheinkersyndrome(Pro102Leu) (2006)
  • Author(s): Arata H, Takashima H, Hirano R, et. al.
  • Journal Title: Neurology 66 Pages: 1672-1678
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Molecular mechanism of rigid spine with muscular dystrophy type l caused by novel mutations of selenoprotein N gene (2006)
  • Author(s): Okamoto Y, Takashima H, Higuchi I, et. al.
  • Journal Title: Neurogenetics 7 Pages: 175-183
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Spinocerebellar ataxia with axonal neuropathy(SCAN1) (2006)
  • Author(s): 高嶋 博、有村 公良
  • Journal Title: 神経進歩 50 Pages: 379-386
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 神経:ニューロパチーの遺伝子学 (2006)
  • Author(s): 橋口 昭大、高嶋 博
  • Journal Title: 最新医学 61 Pages: 2047-2056
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 遺伝性運動・感覚ニューロパチー (2006)
  • Author(s): 高嶋 博、有村 公良
  • Journal Title: 小児内科・増刊号小児疾患の診断治療基準 38 Pages: 726-727
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Association of AKT1 haplotype with the risk of schizophrenia in Iranian population (2006)
  • Author(s): Bajestan, SN., Sabouri, AH., Nakamura, M., Takashima, H., Keikhaee MR., Behdani F., Fayyazi MR., Sargolzaee MR., Bajestan, MN., Sabouri, Z., Khayami, E., Haghighi, S., Hashemi, SB., Eiraku, N., Tufani, H., Najmabadi, H., Arimura, K., Sano, A., Osame, M
  • Journal Title: Am J Med Genet B Neuropsychiatr Genet 141 Pages: 383-6
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Early clinical signs and imaging findings in Gerstmann-Straussler-Scheinker syndrome(Pro102Leu) (2006)
  • Author(s): Arata, H., Takashima, H., Hirano, R., Tomimitsu, H., Machigashira, K., Izumi, K., Kikuno, M., Ng, AR., Umehara, F., Arisato, T., Ohkubo, R., Nakabeppu, Y., Nakajo, M., Osame, M., Arimura, K
  • Journal Title: Neurology 66 Pages: 1672-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Chronic progressive sensory ataxic neuropathy associated with limited systemic sclerosis. (2006)
  • Author(s): Nobuhara Y, Saito M, Arimura K, et al.
  • Journal Title: J Neurol Sci 241(1-2) Pages: 103-106
• [Journal Article] 造伝性ニューロパチーの分子遺伝学 (2006)
  • Author(s): 高嶋 博
  • Journal Title: 臨床神経学 46(1) Pages: 1-18
• [Journal Article] Spinocerebellar ataxia with axonal neuropathy(SCAN1). (2006)
  • Author(s): 高嶋 博, 有村公良
  • Journal Title: 神経研究の進歩 50(3) Pages: 379-386
• [Journal Article] Natural history of spinal and bulbar muscular atrophy (SBMA) : a study of 223 Japanese patients. (2006)
  • Author(s): Atsuta N, Watanabe H, Ito M, Banno H, Sobue G, et al.
  • Journal Title: Brain 129(Pt 6) Pages: 1446-1455
• [Journal Article] Charcot-Marie-Tooth病1Aに対するアスコルビン酸投与の試み (2006)
  • Author(s): 中川正法, 石神紀子, 近藤正樹, 山口達之, 吉田誠克, 有村公良
  • Journal Title: 末梢神経 17(2) Pages: 308-312
  • NAID: 10027578209
• [Journal Article] Periaxin mutation in Japanese patients with Charcot-Marie-Tooth disease. (2006)
  • Author(s): Otagiri T, Sugai K, Kijima K, Hayasaka K, et al.
  • Journal Title: J Hum Genet 51(7) Pages: 625-628
  • NAID: 10017989690
• [Presentation] 糖尿病性神経障害の臨床-日常診療における診断のポイント (2008)
  • Author(s): 有村 公良
  • Organizer: 糖尿病ニューロパシーフォーラム2008
  • Place of Presentation: 大分県日出町
  • Year and Date: 2008-03-14
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 糖尿病性神経障害の最近の知見 (2007)
  • Author(s): 有村 公良
  • Organizer: 第45回日本糖尿病学会九州地方会
  • Place of Presentation: 宮崎市
  • Year and Date: 2007-10-12
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 糖尿病性末梢神経障害の神経生理 (2007)
  • Author(s): 有村 公良
  • Organizer: 第19回臨床神経生理研究会
  • Place of Presentation: 熊本県益城町
  • Year and Date: 2007-08-18
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 糖尿病性神経障害の最近の知見 (2007)
  • Author(s): 有村 公良
  • Organizer: 日本神経学会第86回近畿地方会
  • Place of Presentation: 大阪市
  • Year and Date: 2007-06-23
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Electrophysiology in acquired neuromyotonia (2006)
  • Author(s): Arimura, K
  • Organizer: XI International Congress on Neurorauscular Diseases
  • Place of Presentation: Istanbul,Turkey
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Annual Review神経 (2007)
  • Author(s): 高嶋 博
  • Publisher: 中外医学社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 難治性ニューロパチーの病態に基づく新規治療法の開発平成16-18年度総括研究報告書 (2007)
  • Author(s): 有村 公良、高嶋 博
  • Total Pages: 239
  • Publisher: 厚生労働省精神・神経疾患研究委託費
  • Description: 「研究成果報告書概要(和文)」より