Comprehensive analysis and identification of novel genes in adult leukoencephalopathy by short and long read sequencing.

• Project/Area Number: 20K16581
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Yokohama City University
• Principal Investigator: MIYAKE Ryoko 横浜市立大学, 医学研究科, 客員研究員 (10760184)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: leukoencephalopathy / genetics / exome / long-read

Outline of Research at the Start

白質脳症は大脳白質を病変の主座とする疾患の総称である。原因疾患は多岐にわたり、遺伝性も含め全く病態の異なる疾患が混在する。申請者はこれまでに成人白質脳症の遺伝学的背景解析を行い、神経核内封入体病とcerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathyが成人白質脳症の2大疾患であることを明らかにしてきた。本研究では原因未同定の82例および新規に収集する50例の成人白質脳症の解析を通して、成人白質脳症の遺伝学的背景の包括的な解析、新規原因遺伝子の同定をめざす。

Outline of Final Research Achievements

The disease background of leukoencephalopathy is very diverse, and an accurate diagnosis is essential to consider its appropriate treatment of the disease. However, it is not easy to make a precise diagnosis based on clinical and imaging findings.In this study, we aimed to clarify the genetic background of adult leukoencephalopathy by reanalyzing 81 cases in which the diagnosis was not confirmed in our previous studies and by performing genetic analysis of 50 newly collected cases. In the reanalysis of the previously undetermined cases, copy number analysis, long read sequence analysis, and RNA sequence analysis allowed us to identify the genetic cause in two cases. Further analysis of newly colleted 50 cases identified a genetic cause in 14 cases, 5 of which had neuronal nuclear inclusion body disease and 6 of which had CADASIL.

Academic Significance and Societal Importance of the Research Achievements

我々の先行研究、本研究を通じて、成人白質脳症患者160症例の遺伝学的解析を行い、17例がNIID、17例がCADASILであった。その他は稀少疾患でありCSF1R、EIF2B2、POLR3A、L2HGDH、TUBB4A、YWHAE、DARS2、HTRA1、RRM2B、COL4A1解析のバリアントが原因である症例が1例ずつで、原因が判明したのは44例/160例（27.5％）であった。
本研究により成人白質脳症の遺伝学的背景の一端が明らかとなり、成人白質脳症の診断、治療に有益なデータを提供できたと考えられる。

Research Products

• [Journal Article] Case Report: Anti-MOG Antibody Seroconversion Accompanied by Dimethyl Fumarate Treatment (2021)
  • Author(s): Takahashi Keita、Takeuchi Hideyuki、Fukai Ryoko、Nakamura Haruko、Morihara Keisuke、Higashiyama Yuichi、Takahashi Toshiyuki、Doi Hiroshi、Tanaka Fumiaki
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 625465-625465
  • DOI: 10.3389/fimmu.2021.625465
  • Peer Reviewed / Open Access
• [Journal Article] SGTA associates with intracellular aggregates in neurodegenerative diseases (2021)
  • Author(s): Kubota Shun、Doi Hiroshi、Koyano Shigeru、Tanaka Kenichi、Komiya Hiroyasu、Katsumoto Atsuko、Ikeda Shingo、Hashiguchi Shunta、Nakamura Haruko、Fukai Ryoko、Takahashi Keita、Kunii Misako、Tada Mikiko、Takeuchi Hideyuki、Tanaka Fumiaki
  • Journal Title: Molecular Brain Volume: 14 Issue: 1 Pages: 59-59
  • DOI: 10.1186/s13041-021-00770-1
  • Peer Reviewed / Open Access
• [Journal Article] Reply to "GGC Repeat Expansion of NOTCH2NLC is Rare in European Leukoencephalopathy" (2020)
  • Author(s): Doi H, Okubo M, Fukai R, Fujita A, Mitsuhashi S, Takahashi K, Kunii M, Tada M, Fukuda H, Mizuguchi T, Miyatake S, Miyake N, Sone J, Sobue G, Takeuchi H, Matsumoto N and Tanaka F
  • Journal Title: Ann Neurol Volume: 88 Issue: 3 Pages: 642-643
  • DOI: 10.1002/ana.25819
  • Peer Reviewed