論文 - 石塚 佳奈子
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COVID-19が不安症・ストレス障害に及ぼす影響
石塚佳奈子
臨床精神薬理 24 ( 10 ) 1001 - 1009 2021年10月
担当区分：筆頭著者, 責任著者
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発達障害がある人の抑うつ症状に自己記入式評価尺度を用いる際の注意点
石塚佳奈子
臨床精神薬理 24 ( 8 ) 803 - 809 2021年08月
担当区分：筆頭著者, 責任著者
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Establishment of in-hospital clinical network for patients with neurofibromatosis type 1 in Nagoya University Hospital. 国際誌
Yoshihiro Nishida, Kunihiro Ikuta, Atsushi Natsume, Naoko Ishihara, Maki Morikawa, Hiroyuki Kidokoro, Yukako Muramatsu, Norie Nonobe, Kanako Ishizuka, Takuya Takeichi, Miki Kanbe, Seiji Mizuno, Shiro Imagama, Norio Ozaki
Scientific reports 11 ( 1 ) 11933 - 11933 2021年06月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Neurofibromatosis type 1 (NF1) is a genetic multisystem disorder. Clinicians must be aware of the diverse clinical features of this disorder in order to provide optimal care for it. We have set up an NF1 in-hospital medical care network of specialists regardless of patient age, launching a multidisciplinary approach to the disease for the first time in Japan. From January 2014 to December 2020, 246 patients were enrolled in the NF1 patient list and medical records. Mean age was 26.0 years ranging from 3 months to 80 years. The number of patients was higher as age at first visit was lower. There were 107 males (41%) and 139 females. After 2011, the number of patients has increased since the year when the medical care network was started. Regarding orthopedic signs, scoliosis was present in 60 cases (26%), and bone abnormalities in the upper arm, forearm, and tibia in 8 cases (3.5%). Neurofibromas other than cutaneous neurofibromas were present in 90 cases (39%), and MPNST in 17 cases (7.4%). We launched a multidisciplinary NF1 clinic system for the first time in Japan. For patients with NF1, which is a hereditary and systemic disease associated with a high incidence of malignant tumors, it will be of great benefit when the number of such clinics in Japan and the rest of Asia is increased.
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Depressive mood changes are associated with self-perceptions of ADHD characteristics in adults. 査読あり 国際誌
Kanako Ishizuka, Tomomi Ishiguro, Norio Nomura, Toshiya Inada
Psychiatry research 300 113893 - 113893 2021年06月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌）
Subjective attention deficit/hyperactivity disorder (ADHD) symptoms seen in adult depressive patients have often become a pathophysiological topic in recent years. Screening questionnaires are widely used for detecting ADHD; however, the risk of misdiagnosis exists. The present study examined whether self-perceptions of ADHD-related characteristics were consistent regardless of changes in the severity of depressive symptoms. Between April to October 2018, newly diagnosed depressed outpatients aged 24-59 years with good social functioning and without a history of ADHD were asked to fill out the Adult ADHD Self-Report Scale version 1.1 (ASRS) and the Beck Depression Inventory (BDI) at baseline (n = 726) and 12-week follow-up (n = 202). A statistically significant correlation was found between a change in BDI and ASRS scores (score at baseline minus score at the endpoint; r = .57). In addition, the higher the rate of improvement in BDI, the lower the frequency of positive screening for ADHD by ASRS. This study showed that subjective ADHD symptoms were correlated with depressive states. Diagnostic evaluation of comorbid ADHD using self-report scales in a primary care setting should be made with caution.
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特集 同意取得が困難な事例を対象とした症例報告や研究における問題点と課題 「遺伝負因」の終焉から当事者・家族と進めるゲノム医療へ―ゲノム解析・遺伝カウンセリングに携わる臨床遺伝専門医の立場から― 査読あり
石塚 佳奈子
精神神経学雑誌 123 ( 6 ) 342 - 348 2021年06月
記述言語：日本語 出版者・発行元：(公社)日本精神神経学会
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Peripheral biomarkers of attention-deficit hyperactivity disorder: Current status and future perspective. 国際誌
Nagahide Takahashi, Kanako Ishizuka, Toshiya Inada
Journal of psychiatric research 137 465 - 470 2021年05月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by a persistent pattern of inattention, hyperactivity, and impulsivity. Since the diagnosis of ADHD is defined by operational diagnostic criteria consisting of several clinical symptoms, a number of heterogeneous mechanisms have been considered to be implicated in its pathophysiology. Although no clinically reliable biomarkers are available for the diagnosis of ADHD, several plausible candidate biomarkers have been proposed based on recent advances in biochemistry and molecular biology. This review article summarizes potential peripheral biomarkers associated with ADHD, mainly from recently published case-control studies. These include 1) biochemical markers: neurotransmitters and their receptors, neurotrophic factors, serum electrolytes, and inflammation markers; 2) genetic and epigenetic markers: microRNA, mRNA expression, and peripheral DNA methylation; 3) physiological markers: eye movement and electroencephalography. It also discusses the limitations and future directions of these potential biomarkers for application in clinical practice.
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Preliminary investigation of public perspectives towards psychiatric genetics in Japan. 査読あり 国際誌
Kanako Ishizuka
Asian journal of psychiatry 55 102519 - 102519 2021年01月
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Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder. 国際誌
Hidekazu Kato, Itaru Kushima, Daisuke Mori, Akira Yoshimi, Branko Aleksic, Yoshihiro Nawa, Miho Toyama, Sho Furuta, Yanjie Yu, Kanako Ishizuka, Hiroki Kimura, Yuko Arioka, Keita Tsujimura, Mako Morikawa, Takashi Okada, Toshiya Inada, Masahiro Nakatochi, Keiko Shinjo, Yutaka Kondo, Kozo Kaibuchi, Yasuko Funabiki, Ryo Kimura, Toshimitsu Suzuki, Kazuhiro Yamakawa, Masashi Ikeda, Nakao Iwata, Tsutomu Takahashi, Michio Suzuki, Yuko Okahisa, Manabu Takaki, Jun Egawa, Toshiyuki Someya, Norio Ozaki
Translational psychiatry 10 ( 1 ) 421 - 421 2020年12月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (KDM4C) have been suggested to confer a risk for such disorders. However, rare genetic variants in KDM4C have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in KDM4C and SCZ (p = 0.003) and ASD (p = 0.04). We also observed a significant association between deletions in KDM4C and SCZ (corrected p = 0.04). Next, to explore the contribution of single nucleotide variants in KDM4C, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with KDM4C deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between KDM4C CNVs and these two disorders and for their potential functional effect on histone methylation patterns.
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Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility. 国際誌
Yoshihiro Nawa, Hiroki Kimura, Daisuke Mori, Hidekazu Kato, Miho Toyama, Sho Furuta, Yanjie Yu, Kanako Ishizuka, Itaru Kushima, Branko Aleksic, Yuko Arioka, Mako Morikawa, Takashi Okada, Toshiya Inada, Kozo Kaibuchi, Masashi Ikeda, Nakao Iwata, Michio Suzuki, Yuko Okahisa, Jun Egawa, Toshiyuki Someya, Fumichika Nishimura, Tsukasa Sasaki, Norio Ozaki
Human genome variation 7 ( 1 ) 37 - 37 2020年11月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.
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Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia. 査読あり 国際誌
Kanako Ishizuka, Tomoyuki Yoshida, Takeshi Kawabata, Ayako Imai, Hisashi Mori, Hiroki Kimura, Toshiya Inada, Yuko Okahisa, Jun Egawa, Masahide Usami, Itaru Kushima, Mako Morikawa, Takashi Okada, Masashi Ikeda, Aleksic Branko, Daisuke Mori, Toshiyuki Someya, Nakao Iwata, Norio Ozaki
Journal of neurodevelopmental disorders 12 ( 1 ) 25 - 25 2020年09月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Springer Science and Business Media LLC
<title>Abstract</title>
<sec>
<title>Background</title>
Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in <italic>NRXN1</italic>, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ.
</sec>
<sec>
<title>Methods</title>
To discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced <italic>NRXN1</italic> coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling.
</sec>
<sec>
<title>Results</title>
Through mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of <italic>NRXN1</italic>α isoform<italic>,</italic> as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal.
</sec>
<sec>
<title>Conclusions</title>
The combined data suggest that missense variants in <italic>NRXN1</italic> could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ.
</sec>DOI： 10.1186/s11689-020-09325-2
その他リンク： http://link.springer.com/article/10.1186/s11689-020-09325-2/fulltext.html
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ARHGAP10, which encodes Rho GTPase-activating protein 10, is a novel gene for schizophrenia risk. 査読あり 国際誌
Mariko Sekiguchi, Akira Sobue, Itaru Kushima, Chenyao Wang, Yuko Arioka, Hidekazu Kato, Akiko Kodama, Hisako Kubo, Norimichi Ito, Masahito Sawahata, Kazuhiro Hada, Ryosuke Ikeda, Mio Shinno, Chikara Mizukoshi, Keita Tsujimura, Akira Yoshimi, Kanako Ishizuka, Yuto Takasaki, Hiroki Kimura, Jingrui Xing, Yanjie Yu, Maeri Yamamoto, Takashi Okada, Emiko Shishido, Toshiya Inada, Masahiro Nakatochi, Tetsuya Takano, Keisuke Kuroda, Mutsuki Amano, Branko Aleksic, Takashi Yamomoto, Tetsushi Sakuma, Tomomi Aida, Kohichi Tanaka, Ryota Hashimoto, Makoto Arai, Masashi Ikeda, Nakao Iwata, Teppei Shimamura, Taku Nagai, Toshitaka Nabeshima, Kozo Kaibuchi, Kiyofumi Yamada, Daisuke Mori, Norio Ozaki
Translational psychiatry 10 ( 1 ) 247 - 247 2020年07月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Springer Science and Business Media LLC
Schizophrenia (SCZ) is known to be a heritable disorder; however, its multifactorial nature has significantly hampered attempts to establish its pathogenesis. Therefore, in this study, we performed genome-wide copy-number variation (CNV) analysis of 2940 patients with SCZ and 2402 control subjects and identified a statistically significant association between SCZ and exonic CNVs in the ARHGAP10 gene. ARHGAP10 encodes a member of the RhoGAP superfamily of proteins that is involved in small GTPase signaling. This signaling pathway is one of the SCZ-associated pathways and may contribute to neural development and function. However, the ARHGAP10 gene is often confused with ARHGAP21, thus, the significance of ARHGAP10 in the molecular pathology of SCZ, including the expression profile of the ARHGAP10 protein, remains poorly understood. To address this issue, we focused on one patient identified to have both an exonic deletion and a missense variant (p.S490P) in ARHGAP10. The missense variant was found to be located in the RhoGAP domain and was determined to be relevant to the association between ARHGAP10 and the active form of RhoA. We evaluated ARHGAP10 protein expression in the brains of reporter mice and generated a mouse model to mimic the patient case. The model exhibited abnormal emotional behaviors, along with reduced spine density in the medial prefrontal cortex (mPFC). In addition, primary cultured neurons prepared from the mouse model brain exhibited immature neurites in vitro. Furthermore, we established induced pluripotent stem cells (iPSCs) from this patient, and differentiated them into tyrosine hydroxylase (TH)-positive neurons in order to analyze their morphological phenotypes. TH-positive neurons differentiated from the patient-derived iPSCs exhibited severe defects in both neurite length and branch number; these defects were restored by the addition of the Rho-kinase inhibitor, Y-27632. Collectively, our findings suggest that rare ARHGAP10 variants may be genetically and biologically associated with SCZ and indicate that Rho signaling represents a promising drug discovery target for SCZ treatment.
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【その定説は本当ですか?】注意欠如多動症の診断と薬物療法は過少か?過剰か? 招待あり
石塚 佳奈子
臨床精神薬理 23 ( 6 ) 633 - 641 2020年06月
担当区分：筆頭著者, 責任著者 記述言語：日本語 出版者・発行元：(株)星和書店
ADHDはDSM-5で神経発達症の1つに組み込まれ、成人期まで問題が続く慢性疾患と認識されるようになった。ADHDは生物学的基盤と環境が複雑かつ力動的に相互作用する多因子的な疾患概念である。生活している限り環境との齟齬は生じうるため、小児期の一時的な介入は必ずしも長期予後を改善しない。ライフコースに沿った継続的な患者-治療者関係が必要な疾患である。ADHDの疾患概念の拡がりや疾患啓発は、見過ごされてきた群への適切な診断や介入につながった一方で、鑑別を欠く過剰なADHD診断と薬物療法を引き起こした。本稿ではADHD概念を臨床でどのように活かすのか、診断や薬物療法の過剰、過少に影響しうる要因を通じて検討したい。(著者抄録)
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Generation and analysis of novel Reln-deleted mouse model corresponding to exonic Reln deletion in schizophrenia. 査読あり 国際誌
Masahito Sawahata, Daisuke Mori, Yuko Arioka, Hisako Kubo, Itaru Kushima, Kanako Kitagawa, Akira Sobue, Emiko Shishido, Mariko Sekiguchi, Akiko Kodama, Ryosuke Ikeda, Branko Aleksic, Hiroki Kimura, Kanako Ishizuka, Taku Nagai, Kozo Kaibuchi, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki
Psychiatry and clinical neurosciences 74 ( 5 ) 318 - 327 2020年05月
記述言語：英語 掲載種別：研究論文（学術雑誌）
AIM: A Japanese individual with schizophrenia harboring a novel exonic deletion in RELN was recently identified by genome-wide copy-number variation analysis. Thus, the present study aimed to generate and analyze a model mouse to clarify whether Reln deficiency is associated with the pathogenesis of schizophrenia. METHODS: A mouse line with a novel RELN exonic deletion (Reln-del) was established using the CRISPR/Cas9 method to elucidate the underlying molecular mechanism. Subsequently, general behavioral tests and histopathological examinations of the model mice were conducted and phenotypic analysis of the cerebellar granule cell migration was performed. RESULTS: The phenotype of homozygous Reln-del mice was similar to that of reeler mice with cerebellar atrophy, dysplasia of the cerebral layers, and abrogated protein levels of cerebral reelin. The expression of reelin in heterozygous Reln-del mice was approximately half of that in wild-type mice. Conversely, behavioral analyses in heterozygous Reln-del mice without cerebellar atrophy or dysplasia showed abnormal social novelty in the three-chamber social interaction test. In vitro reaggregation formation and neuronal migration were severely altered in the cerebellar cultures of homozygous Reln-del mice. CONCLUSION: The present results in novel Reln-del mice modeled after our patient with a novel exonic deletion in RELN are expected to contribute to the development of reelin-based therapies for schizophrenia.
DOI： 10.1111/pcn.12993
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児童思春期のうつ病に対する抗うつ薬療法の是非 招待あり
松川剛, 石塚佳奈子, 稲田俊也
臨床精神薬理 23 ( 6 ) 627 - 632 2020年05月
担当区分：責任著者
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Clinical Features and Long-Term Outcomes of Living Donors of Liver Transplantation Who Developed Psychiatric Disorders. 査読あり 国際誌
Masato Shizuku, Hideya Kamei, Hiroyuki Kimura, Nobuhiko Kurata, Kanta Jobara, Atsushi Yoshizawa, Kanako Ishizuka, Aoi Okada, Shinichi Kishi, Norio Ozaki, Yasuhiro Ogura
Annals of transplantation 25 e918500 - 7 2020年01月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：International Scientific Information, Inc.
BACKGROUND In the field of living donor liver transplantation (LDLT), it is important to ensure donor's psychological well-being. We report on clinical features and long-term outcomes of LDLT donors who developed psychiatric disorders after their donor operations. Additionally, we compare patient backgrounds, as well as surgical and perioperative aspects between LDLT donors with and without postoperative psychiatric complications. MATERIAL AND METHODS Between November 1998 and March 2018, we identified 254 LDLT donors at our hospital. Among these, we investigated those who had newly developed psychiatric complications and required psychiatric treatment after donor operation. RESULTS The median duration of follow-up was 4 years. Sixty-five donors were lost to follow-up. Eight donors (3.1%) developed postoperative psychiatric complications, including major depressive disorder in 4, panic disorder in 2, conversion disorder and panic disorder in 1, and adjustment disorder in 1. The median duration from donor surgery to psychiatric diagnosis was 104.5 days (range, 12 to 657 days) and the median treatment duration was 18 months (range, 3 to 168 months). Of those, 3 donors required psychiatric treatment over 10 years, and 4 donors remained under treatment. The duration of hospital stay after donor operation was significantly longer and perioperative complications with Clavien classification greater than grade IIIa were more frequent in donors with psychiatric complications than in those without psychiatric complications (P=0.02 and P=0.006, respectively). CONCLUSIONS Accurate diagnosis and appropriate treatment for psychiatric disorders by psychiatrists and psychologists are important during LDLT donor follow-up. Minimization of physiological complications might be important to prevent postoperative psychiatric complications in LDLT donors.
DOI： 10.12659/AOT.918500
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分子精神医学の気になる進歩：ゲノム医学領域の進展を中心に 招待あり
瀬名波徹, 石塚佳奈子, 久島周, 尾崎紀夫
精神科 36 ( 1 ) 92 - 97 2020年01月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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「遺伝」を継承と多様性で語る精神科医療に―精神疾患の遺伝要因を当事者やその家族とどう話し合うか― 査読あり
石塚佳奈子, 尾崎紀夫
日本精神神経学会雑誌 121 ( 8 ) 602 - 611 2019年08月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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Assessment of a glyoxalase I frameshift variant, p.P122fs, in Japanese patients with schizophrenia. 国際誌
Kanako Ishizuka, Hiroki Kimura, Itaru Kushima, Toshiya Inada, Yuko Okahisa, Masashi Ikeda, Nakao Iwata, Daisuke Mori, Branko Aleksic, Norio Ozaki
Psychiatric genetics 28 ( 5 ) 90 - 93 2018年10月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Enhanced carbonyl stress has been observed in a subgroup of patients with schizophrenia. Glyoxalase I, which is encoded by GLO1, is an enzyme that protects against carbonyl stress. In this study, we focused on the association between rare genetic variants of GLO1 and schizophrenia. First, we identified one heterozygous frameshift variant, p.P122fs, in 370 Japanese schizophrenia cases with allele frequencies of up to 1% by exon-targeted mutation screening of GLO1. We then performed an association analysis on 1282 cases and 1764 controls with this variant. The variant was found in three cases and eight controls. There was no statistically significant association between p.P122fs in GLO1 and schizophrenia (P=0.25). This frameshift variant in GLO1 might occur at near-polymorphic frequencies in the Japanese population, although further investigations using larger samples and biological analyses are needed to exclude the possibility of a low-penetrance genetic risk associated with this variant.
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Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. 査読あり 国際誌
Itaru Kushima, Branko Aleksic, Masahiro Nakatochi, Teppei Shimamura, Takashi Okada, Yota Uno, Mako Morikawa, Kanako Ishizuka, Tomoko Shiino, Hiroki Kimura, Yuko Arioka, Akira Yoshimi, Yuto Takasaki, Yanjie Yu, Yukako Nakamura, Maeri Yamamoto, Tetsuya Iidaka, Shuji Iritani, Toshiya Inada, Nanayo Ogawa, Emiko Shishido, Youta Torii, Naoko Kawano, Yutaka Omura, Toru Yoshikawa, Tokio Uchiyama, Toshimichi Yamamoto, Masashi Ikeda, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Ayako Nunokawa, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Akiko Kobori, Michio Suzuki, Tsutomu Takahashi, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Tsukasa Sasaki, Hitoshi Kuwabara, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Yosuke Eriguchi, Seico Benner, Masaki Kojima, Walid Yassin, Toshio Munesue, Shigeru Yokoyama, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Makoto Ishitobi, Tetsuro Ohmori, Shusuke Numata, Takeo Yoshikawa, Tomoko Toyota, Kazuhiro Yamakawa, Toshimitsu Suzuki, Yushi Inoue, Kentaro Nakaoka, Yu-Ichi Goto, Masumi Inagaki, Naoki Hashimoto, Ichiro Kusumi, Shuraku Son, Toshiya Murai, Tempei Ikegame, Naohiro Okada, Kiyoto Kasai, Shohko Kunimoto, Daisuke Mori, Nakao Iwata, Norio Ozaki
Cell reports 24 ( 11 ) 2838 - 2856 2018年09月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders.
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Single-cell trajectory analysis of human homogenous neurons carrying a rare RELN variant. 国際誌
Yuko Arioka, Emiko Shishido, Hisako Kubo, Itaru Kushima, Akira Yoshimi, Hiroki Kimura, Kanako Ishizuka, Branko Aleksic, Takuji Maeda, Mitsuru Ishikawa, Naoko Kuzumaki, Hideyuki Okano, Daisuke Mori, Norio Ozaki
Translational psychiatry 8 ( 1 ) 129 - 129 2018年07月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Reelin is a protein encoded by the RELN gene that controls neuronal migration in the developing brain. Human genetic studies suggest that rare RELN variants confer susceptibility to mental disorders such as schizophrenia. However, it remains unknown what effects rare RELN variants have on human neuronal cells. To this end, the analysis of human neuronal dynamics at the single-cell level is necessary. In this study, we generated human-induced pluripotent stem cells carrying a rare RELN variant (RELN-del) using targeted genome editing; cells were further differentiated into highly homogeneous dopaminergic neurons. Our results indicated that RELN-del triggered an impaired reelin signal and decreased the expression levels of genes relevant for cell movement in human neurons. Single-cell trajectory analysis revealed that control neurons possessed directional migration even in vitro, while RELN-del neurons demonstrated a wandering type of migration. We further confirmed these phenotypes in neurons derived from a patient carrying the congenital RELN-del. To our knowledge, this is the first report of the biological significance of a rare RELN variant in human neurons based on individual neuron dynamics. Collectively, our approach should be useful for studying reelin function and evaluating mental disorder susceptibility, focusing on individual human neuronal migration.
