Faculty Profiles - OGI Tomoo

Loss of neuronal activity facilitates surface accumulation of p75NTR and cell death in avian cochlear nucleus Open Access

Ryosuke Sato, Ryota Adachi, Norihiko Yokoi, Keita Tsujimura, Ryo Egawa, Yuichiro Hara, Yuko Fukata, Masaki Fukata, Tomoo Ogi, Michihiko Sone, Hiroshi Kuba

Neuroscience Research Vol. 213 page： 23 - 34 2025.4

Novel FBN1 intron variant causes isolated ectopia lentis via in-frame exon skipping Open Access

Shimizu, N; Mashimo, Y; Yokouchi, H; Nishio, Y; Sawai, S; Ichikawa, T; Ogi, T; Baba, T; Onouchi, Y

JOURNAL OF HUMAN GENETICS Vol. 70 ( 4 ) page： 199 - 205 2025.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Human Genetics

Mutations in fibrillin-1 (FBN1) cause various clinical conditions, such as Marfan syndrome (MFS). However, the genotype–phenotype relationships underlying MFS and other conditions relevant to FBN1 mutations have not been fully elucidated. We performed whole-exome sequencing on three participants, including an affected mother–daughter pair, in a three-generation Japanese family with isolated ectopia lentis (IEL). The sequencing identified a novel single-nucleotide variant (c.1327+3A>C) in intron 11 of FBN1 that was shared between the two patients. We confirmed the co-segregation of the variant with IEL in two additional affected relatives in the family. The Combined Annotation-Dependent Depletion score of the variant was 26.1, which was indicated by SpliceAI to influence splicing, with a score of 0.93. Reverse transcription-polymerase chain reaction (RT-PCR) of mRNAs isolated from peripheral blood mononuclear cells revealed aberrant bands in all four affected individuals. Subsequent sequencing revealed that these bands originated from FBN1 transcripts lacking exon 11. The causality of the variant in the skipping of exon 11, which results in an in-frame deletion of 60 amino acids corresponding to the “hinge” region of FBN1 protein, was confirmed in a minigene experiment. Interestingly, the same result was observed for a minigene for c.1327+1G>A, a variant previously identified in two unrelated EL families without MFS manifestations. These results suggest that the c.1327+3A>C mutation in FBN1 likely leads to IEL. The findings expand our knowledge of FBN1 and provide insights into FBN1-related diseases.

DOI： 10.1038/s10038-025-01318-0

Estimating the proportions of allele frequencies for SERPINA12 pathogenic variants in Japanese patients with Nagashima-type palmoplantar keratosis/keratoderma. International journal

Aoi Ebata, Takuya Takeichi, Kazuki Nishida, Basile Chretien, Akira Miyazaki, Takenori Yoshikawa, Yuika Suzuki, Kana Tanahashi, Ryo Fukaura, Mariko Seishima, Yasushi Suga, Yoshinao Muro, Yuka Nakazawa, Tomoo Ogi, Masashi Akiyama

The British journal of dermatology 2025.3

Whole-genome sequencing analysis of Japanese autism spectrum disorder trios Open Access

Furukawa, S; Kushima, I; Kato, H; Kimura, H; Nawa, Y; Aleksic, B; Banno, M; Yamamoto, M; Uematsu, M; Nagasaki, Y; Ogi, T; Ozaki, N; Ikeda, M

PSYCHIATRY AND CLINICAL NEUROSCIENCES Vol. 79 ( 3 ) page： 87 - 97 2025.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Psychiatry and Clinical Neurosciences

Aim: Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. Conducting the first comprehensive whole-genome sequencing (WGS) analysis of Japanese ASD trios, this study aimed to elucidate the clinical significance of pathogenic variants and enhance the understanding of ASD pathogenesis. Methods: WGS was performed on 57 Japanese patients with ASD and their parents, investigating variants ranging from single-nucleotide variants to structural variants (SVs), short tandem repeats (STRs), mitochondrial variants, and polygenic risk score (PRS). Results: Potentially pathogenic variants that could explain observed phenotypes were identified in 18 patients (31.6%) overall and in 10 of 23 patients (43.5%) with comorbid intellectual developmental disorder (IDD). De novo variants in PTEN, CHD7, and HNRNPH2 were identified in patients referred for genetic counseling who exhibited previously reported phenotypes, including one patient with ASD who had profound IDD and macrocephaly with PTEN L320S. Analysis of the AlphaFold3 protein structure indicated potential inhibition of intramolecular interactions within PTEN. SV analysis identified deletions in ARHGAP11B and TMLHE. A pathogenic de novo mitochondrial variant was identified in a patient with ASD who had a history of encephalitis and cognitive decline. GO enrichment analysis of genes with nonsense variants and missense variants (Missense badness, PolyPhen-2, and Constraint >1) showed associations with regulation of growth and ATP-dependent chromatin remodeler activity. No reportable results were obtained in the analysis of STR and PRS. Conclusion: Characterizing the comprehensive genetic architecture and phenotypes of ASD is a fundamental step towards unraveling its complex biology.

DOI： 10.1111/pcn.13767

Pathophysiological significance of the p.E31G variant in RAC1 responsible for a neurodevelopmental disorder with microcephaly Reviewed

WHOLE GENOME SEQUENCING ANALYSIS OF JAPANESE ASD TRIOS: UNRAVELING PATHOGENIC VARIANTS Open Access

Furukawa, S; Kushima, I; Kimura, H; Kato, H; Nawa, Y; Aleksic, B; Ogi, T; Ozaki, N; Ikeda, M

INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY Vol. 28 page： i59 - i59 2025.2

Prenatal inflammation impairs early CD11c-positive microglia induction and delays myelination in neurodevelopmental disorders. International journal Open Access

Kazuya Fuma, Yukako Iitani, Kenji Imai, Takafumi Ushida, Sho Tano, Kosuke Yoshida, Akira Yokoi, Rika Miki, Hiroyuki Kidokoro, Yoshiaki Sato, Yuichiro Hara, Tomoo Ogi, Kohei Nomaki, Makoto Tsuda, Okiru Komine, Koji Yamanaka, Hiroaki Kajiyama, Tomomi Kotani

Communications biology Vol. 8 ( 1 ) page： 75 - 75 2025.1

Language：English Publishing type：Research paper (scientific journal)

Histological chorioamnionitis (HCA) is a form of maternal immune activation (MIA) linked to an increased risk of neurodevelopmental disorders in offspring. Our previous study identified neurodevelopmental impairments in an MIA mouse model mimicking HCA. Thus, this study investigated the role of CD11c+ microglia, key contributors to myelination through IGF-1 production, in this pathology. In the mouse model, the CD11c+ microglial population was significantly lower in the MIA group than in the control group on postnatal day 3 (PN3d). Furthermore, myelination-related protein levels significantly decreased in the MIA group at PN8d. In humans, preterm infants with HCA exhibited higher IL-6 and IL-17A cord-serum levels and lower IGF-1 levels than those without HCA, followed by a higher incidence of delayed myelination on magnetic resonance imaging at the term-equivalent age. In silico analysis revealed that the transient induction of CD11c+ microglia during early development occurred similarly in mice and humans. Notably, a lack of high CD11c+ microglial population has been observed in children with neurodevelopmental disorders. This study reports impaired induction of CD11c+ microglia during postnatal development in a mouse model of MIA associated with delayed myelination. Our findings may inform strategies for improving outcomes in infants with HCA.

DOI： 10.1038/s42003-025-07511-3

Nishikawa, M; Hayashi, S; Nakayama, A; Nishio, Y; Shiraki, A; Ito, H; Maruyama, K; Muramatsu, Y; Ogi, T; Mizuno, S; Nagata, K

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE Vol. 1871 ( 1 ) 2025.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Biochimica et Biophysica Acta - Molecular Basis of Disease

RAC1 encodes a Rho family small GTPase that regulates actin cytoskeletal reorganization and intracellular signaling pathways. Pathogenic RAC1 variants lead to a neurodevelopmental disorder with diverse phenotypic manifestations, including abnormalities in brain size and facial dysmorphism. However, the underlying pathophysiological mechanisms have yet to be elucidated. Here, we present the case of a school-aged male who exhibited global developmental delay, intellectual disability, and acquired microcephaly. Through whole exome sequencing, we identified a novel de novo variant in RAC1, (NM_006908.5): c.92 A > G,p.(E31G). We then examined the pathophysiological significance of the p.E31G variant by focusing on brain development. Biochemical analyses revealed that the recombinant RAC1-E31G had no discernible impact on the intrinsic GDP/GTP exchange activity. However, it exhibited a slight inhibitory effect on GTP hydrolysis. Conversely, it demonstrated a typical response to both a guanine-nucleotide exchange factor and a GTPase-activating protein. In transient expression analyses using COS7 cells, RAC1-E31G exhibited minimal interaction with the downstream effector PAK1, even in its GTP-bound state. Additionally, overexpression of RAC1-E31G was observed to exert a weak inhibitory effect on the differentiation of primary cultured hippocampal neurons. Moreover, in vivo studies employing in utero electroporation revealed that acute expression of RAC1-E31G resulted in impairments in axonal elongation and dendritic arborization in the young adult stage. These findings suggest that the p.E31G variant functions as a dominant-negative version in the PAK1-mediated signaling pathway and is responsible for the clinical features observed in the patient under investigation, namely microcephaly and intellectual disability.

DOI： 10.1016/j.bbadis.2024.167520

Desulfovibrio falkowii sp. nov., Porphyromonas miyakawae sp. nov., Mediterraneibacter flintii sp. nov. and Owariibacterium komagatae gen. nov., sp. nov., isolated from human faeces. Open Access

Transcription‐coupled repair – mechanisms of action, regulation, and associated human disorders Open Access

Yuka Nakazawa, Yasuyoshi Oka, Tomoko Matsunaga, Tomoo Ogi

FEBS Letters Vol. 599 ( 2 ) page： 166 - 167 2025.1

Hamaguchi T, Ohara M, Hisatomi A, Sekiguchi K, Takeda JI, Ueyama J, Ito M, Nishiwaki H, Ogi T, Hirayama M, Ohkuma M, Sakamoto M, Ohno K

International journal of systematic and evolutionary microbiology Vol. 75 ( 1 ) 2025.1

Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Systematic and Evolutionary Microbiology

Small, obligately anaerobic strains 13CB8CT, 13CB11CT, 13CB18CT and 13GAM1GT were isolated from a faecal sample in a patient with Parkinson’s disease with a history of duodenal resection. After conducting a comprehensive polyphasic taxonomic analysis including genomic analysis, we propose the establishment of one new genus and four new species. The novel bacteria are Desulfovibrio falkowii sp. nov. (type strain JCM 36128T = DSM 116810T), Porphyromonas miyakawae sp. nov. (type strain JCM 36129T = DSM 116947T), Mediterraneibacter flintii sp. nov. (type strain JCM 36130T = DSM 116866T) and Owariibacterium komaga-tae gen. nov. sp. nov. (type strain JCM 36131T = DSM 116982T), respectively.

DOI： 10.1099/ijsem.0.006636

Open Access

Heavy water inhibits DNA double-strand break repairs and disturbs cellular transcription, presumably via quantum-level mechanisms of kinetic isotope effects on hydrolytic enzyme reactions Reviewed

Clinical and molecular overlap between nucleotide excision repair (NER) disorders and DYRK1A haploinsufficiency syndrome. Open Access

Le May N, Courraud J, Boujelbène I, Obringer C, Ogi T, Lehmann AR, Laffargue F, Lehalle D, Mizuno S, Mohammed S, Ormières C, Willems M, Laugel V, Calmels N

Frontiers in neuroscience Vol. 19 page： 1554093 2025

Neonatal myoclonus in Bryant-Li-Bhoj syndrome associated with a novel H3F3A variant Open Access

Hojo, M; Soma, N; Yamada, K; Kobayashi, Y; Miura, M; Fujii, H; Nyuzuki, H; Nishio, Y; Oso, T; Ogi, T; Ikeuchi, T; Tohyama, J

HUMAN GENOME VARIATION Vol. 11 ( 1 ) page： 45 2024.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Human Genome Variation

Bryant-Li-Bhoj syndrome (BLBS; OMIM # 619720, 619721), caused by germline H3F3A and H3F3B variants encoding histone H3.3, is characterized by mild to severe developmental delay, intellectual disability, failure to thrive, muscle tone abnormalities, and dysmorphic facial features. Here, we present a Japanese patient with a novel heterozygous p.A48G variant in H3F3A, displaying previously unrecognized symptoms of neonatal myoclonus. This case helps broaden the phenotypic spectrum of BLBS.

DOI： 10.1038/s41439-024-00303-x

ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice. International journal Open Access

Mai Horiuchi, Seiji Watanabe, Okiru Komine, Eiki Takahashi, Kumi Kaneko, Shigeyoshi Itohara, Mayuko Shimada, Tomoo Ogi, Koji Yamanaka

Acta neuropathologica communications Vol. 12 ( 1 ) page： 184 - 184 2024.11

Language：English Publishing type：Research paper (scientific journal)

Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and its pathogenic mechanism is mediated by both loss-of-function and gain-of-toxicity of TDP-43. However, the role of TDP-43 gain-of-toxicity in oligodendrocytes remains unclear. To investigate the impact of excess TDP-43 on oligodendrocytes, we established transgenic mice overexpressing the ALS-linked mutant TDP-43M337V in oligodendrocytes through crossbreeding with Mbp-Cre mice. Two-step crossbreeding of floxed TDP-43M337V and Mbp-Cre mice resulted in the heterozygous low-level systemic expression of TDP-43M337V with (Cre-positive) or without (Cre-negative) oligodendrocyte-specific overexpression of TDP-43M337V. Although Cre-negative mice also exhibit subtle motor dysfunction, TDP-43M337V overexpression in oligodendrocytes aggravated clasping signs and gait disturbance accompanied by myelin pallor in the corpus callosum and white matter of the lumbar spinal cord in Cre-positive mice. RNA sequencing analysis of oligodendrocyte lineage cells isolated from whole brains of 12-month-old transgenic mice revealed downregulation of myelinating oligodendrocyte marker genes and cholesterol-related genes crucial for myelination, along with marked upregulation of apoptotic pathway genes. Immunofluorescence staining showed cleaved caspase 3-positive apoptotic oligodendrocytes surrounded by activated microglia and astrocytes in aged transgenic mice. Collectively, our findings demonstrate that an excess amount of ALS-linked mutant TDP-43 expression in oligodendrocytes exacerbates motor dysfunction in mice, likely through oligodendrocyte dysfunction and neuroinflammation. Therefore, targeting oligodendrocyte protection, particularly through ameliorating TDP-43 pathology, could represent a potential therapeutic approach for ALS.

DOI： 10.1186/s40478-024-01893-x

Yasuda T., Nakajima N., Ogi T., Yanaka T., Tanaka I., Gotoh T., Kagawa W., Sugasawa K., Tajima K.

PLoS ONE Vol. 19 ( 10 October ) 2024.10

Language：English Publishing type：Research paper (scientific journal) Publisher：PLoS ONE

Heavy water, containing the heavy hydrogen isotope, is toxic to cells, although the underlying mechanism remains incompletely understood. In addition, certain enzymatic proton transfer reactions exhibit kinetic isotope effects attributed to hydrogen isotopes and their temperature dependencies, indicative of quantum tunneling phenomena. However, the correlation between the biological effects of heavy water and the kinetic isotope effects mediated by hydrogen isotopes remains elusive. In this study, we elucidated the kinetic isotope effects arising from hydrogen isotopes of water and their temperature dependencies in vitro, focusing on deacetylation, DNA cleavage, and protein cleavage, which are crucial enzymatic reactions mediated by hydrolysis. Intriguingly, the intracellular isotope effects of heavy water, related to the in vitro kinetic isotope effects, significantly impeded multiple DNA double-strand break repair mechanisms crucial for cell survival. Additionally, heavy water exposure enhanced histone acetylation and associated transcriptional activation in cells, consistent with the in vitro kinetic isotope effects observed in histone deacetylation reactions. Moreover, as observed for the in vitro kinetic isotope effects, the cytotoxic effect on cell proliferation induced by heavy water exhibited temperature-dependency. These findings reveal the substantial impact of heavy water-induced isotope effects on cellular functions governed by hydrolytic enzymatic reactions, potentially mediated by quantum-level mechanisms underlying kinetic isotope effects.

DOI： 10.1371/journal.pone.0309689

Treatment-resistant schizophrenia with 22q11.2 deletion and additional genetic defects Reviewed

Furukawa, S; Arafuka, S; Kato, H; Ogi, T; Ozaki, N; Ikeda, M; Kushima, I

NEUROPSYCHOPHARMACOLOGY REPORTS 2024.8

Language：English Publishing type：Research paper (scientific journal) Publisher：Neuropsychopharmacology Reports

We report a case of a 61-year-old female with 22q11.2 deletion syndrome (22q11.2DS) and a novel heterozygous nonsense variant in MAP1A, identified through whole-genome sequencing (WGS). The patient presented with intellectual developmental disorder, treatment-resistant schizophrenia (SCZ), and multiple congenital anomalies. Despite aggressive pharmacotherapy, she experienced persistent auditory hallucinations and negative symptoms. WGS revealed a 3 Mb deletion at 22q11.2 and a nonsense variant in MAP1A (c.4652T>G, p.Leu1551*). MAP1A, encoding microtubule-associated protein 1A, is crucial for axon and dendrite development and has been implicated in autism spectrum disorder and SCZ. The MAP1A variant may contribute to the severe psychiatric phenotype, as it is thought to influence synaptic plasticity, a process also affected by 22q11.2 deletion. This case highlights the importance of WGS in identifying additional pathogenic variants that may explain phenotypic variability in 22q11.2DS. Thus, WGS can lead to a better understanding of the genetic architecture of 22q11.2DS. However, further studies are needed to elucidate the role of secondary genetic contributors in the diverse clinical presentations of 22q11.2DS.

DOI： 10.1002/npr2.12477

The small CRL4CSA ubiquitin ligase component DDA1 regulates transcription-coupled repair dynamics Reviewed

Localized epidermolysis bullosa simplex caused by a previously unreported substitution in the linker 12 domain of keratin 14. Reviewed International journal

Miyu Misaki, Takuya Takeichi, Michiya Omi, Yasutoshi Ito, Tomoo Ogi, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology Vol. 51 ( 8 ) page： e264 - e265 2024.8

Schiffmacher, DAL; Lee, SH; Kliza, KW; Theil, AF; Akita, M; Helfricht, A; Bezstarosti, K; Gonzalo-Hansen, C; van Attikum, H; Verlaan-de Vries, M; Vertegaal, ACO; Hoeijmakers, JHJ; Marteijn, JA; Lans, H; Demmers, JAA; Vermeulen, M; Sixma, TK; Ogi, T; Vermeulen, W; Pines, A

NATURE COMMUNICATIONS Vol. 15 ( 1 ) 2024.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Communications

Transcription-blocking DNA lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which removes a broad spectrum of DNA lesions to preserve transcriptional output and thereby cellular homeostasis to counteract aging. TC-NER is initiated by the stalling of RNA polymerase II at DNA lesions, which triggers the assembly of the TC-NER-specific proteins CSA, CSB and UVSSA. CSA, a WD40-repeat containing protein, is the substrate receptor subunit of a cullin-RING ubiquitin ligase complex composed of DDB1, CUL4A/B and RBX1 (CRL4CSA). Although ubiquitination of several TC-NER proteins by CRL4CSA has been reported, it is still unknown how this complex is regulated. To unravel the dynamic molecular interactions and the regulation of this complex, we apply a single-step protein-complex isolation coupled to mass spectrometry analysis and identified DDA1 as a CSA interacting protein. Cryo-EM analysis shows that DDA1 is an integral component of the CRL4CSA complex. Functional analysis reveals that DDA1 coordinates ubiquitination dynamics during TC-NER and is required for efficient turnover and progression of this process.

DOI： 10.1038/s41467-024-50584-7

Dyssegmental dysplasia Rolland-Desbuquois type is caused by pathogenic variants in HSPG2 - a founder haplotype shared in five patients. Reviewed International journal

Paniz Farshadyeganeh, Takahiro Yamada, Hirofumi Ohashi, Gen Nishimura, Hiroki Fujita, Yuriko Oishi, Misa Nunode, Shuku Ishikawa, Jun Murotsuki, Yuri Yamashita, Shiro Ikegawa, Tomoo Ogi, Eri Arikawa-Hirasawa, Kinji Ohno

Journal of human genetics Vol. 69 ( 6 ) page： 235 - 244 2024.6

Language：English Publishing type：Research paper (scientific journal)

Dyssegmental dysplasia (DD) is a severe skeletal dysplasia comprised of two subtypes: lethal Silverman-Handmaker type (DDSH) and nonlethal Rolland-Desbuquois type (DDRD). DDSH is caused by biallelic pathogenic variants in HSPG2 encoding perlecan, whereas the genetic cause of DDRD remains undetermined. Schwartz-Jampel syndrome (SJS) is also caused by biallelic pathogenic variants in HSPG2 and is an allelic disorder of DDSH. In SJS and DDSH, 44 and 8 pathogenic variants have been reported in HSPG2, respectively. Here, we report that five patients with DDRD carried four pathogenic variants in HSPG2: c.9970 G > A (p.G3324R), c.559 C > T (p.R187X), c7006 + 1 G > A, and c.11562 + 2 T > G. Two patients were homozygous for p.G3324R, and three patients were heterozygous for p.G3324R. Haplotype analysis revealed a founder haplotype spanning 85,973 bp shared in the five patients. SJS, DDRD, and DDSH are allelic disorders with pathogenic variants in HSPG2.

DOI： 10.1038/s10038-024-01229-6