Faculty Profiles - OGI Tomoo

MVD-Nonsyndromic Epidermal Differentiation Disorder With a Previously Unreported Splice Variant in MVD Followed by Bullous Pemphigoid

CiNii Research

Miyazaki, A; Takeichi, T; Ishii, N; Ogi, T; Muro, Y; Akiyama, M

JOURNAL OF DERMATOLOGY 2025.10

XP-J, a ninth xeroderma pigmentosum complementation group, results from mutations in GTF2H4, encoding TFIIH-p52 subunit.

Fassihi H, Mohammed S, Nakazawa Y, Fawcett H, Turner S, Palfrey J, Garrood I, Abiona A, Morley AM, Shimada M, Kato K, Lehmann AR, Ogi T

The Journal of clinical investigation 2025.9

TFIIH-p52∆C defines a ninth xeroderma pigmentosum complementation-group XP-J and restores TFIIH stability to p8-defective trichothiodystrophy.

Nakazawa Y, Ye L, Oka Y, Morinaga H, Kato K, Shimada M, Tsukada K, Tsujikawa K, Nishio Y, Fassihi H, Mohammed S, Lehmann AR, Ogi T

The Journal of clinical investigation 2025.9

Transient Dietary Intervention Induces Healthy Adipose Tissue Expansion and Metabolically Healthy Obesity in Mice

Wada, E; Hosono, H; Tanaka, M; Miyakawa, F; Ochi, K; Kohda, H; Tanno, S; Shimano, R; Ito, A; Kitaura, Y; Ichihara, K; Matsumoto, A; Ogi, T; Satoh-Asahara, N; Murohara, T; Suganami, T

FASEB JOURNAL Vol. 39 ( 14 ) page： e70847 2025.7

Language：English Publishing type：Research paper (scientific journal) Publisher：FASEB Journal

As obesity progresses, dynamic tissue remodeling of adipose tissue occurs over time, that is, adipocyte hypertrophy, chronic inflammation, and interstitial fibrosis. Some obese individuals exhibit healthy adipose tissue expansion, characterized by modest inflammation and fibrosis despite adipocyte hypertrophy, resulting in “Metabolically Healthy Obesity (MHO)”. In this study, we investigated the effects of transient weight loss on adipose tissue remodeling during the development of obesity. Male C57BL6/J mice received various types of transient weight loss treatments during diet-induced obesity. A 2-week weight loss intervention during the inflammatory phase promoted healthy adipose tissue expansion, reduced ectopic lipid accumulation, and improved glucose metabolism. In contrast, protocols with shorter duration and delayed intervention, failed to induce MHO. Since serum concentrations of ketone bodies were elevated during weight loss, we examined the effects of hyperketonemia on obesity-induced adipose tissue remodeling. Transient treatment with 1,3-butanediol (BD), which increased serum ketone body concentrations to levels similar to those observed during weight loss, induced healthy adipose tissue expansion and reduced hepatic steatosis even during continuous high-fat diet (HFD) feeding. Ketone bodies effectively suppressed activation of adipose tissue fibroblasts in vivo and in vitro. This study provides evidence that an appropriate dietary intervention can promote healthy adipose tissue expansion in mice, even after the regaining of weight, thereby leading to MHO. As the underlying mechanism, our data revealed a key role for ketone bodies in suppressing activation of adipose tissue fibroblasts. This study paves the way for nutritional approaches to induce MHO.

DOI： 10.1096/fj.202501121R

Ritscher-Schinzel syndrome can be characterized as an endosomal recyclinopathy

Kato, K; Nishio, Y; McMillan, KJ; Al-Maraghi, A; Kroes, HY; Abdel-Hamid, MS; Jones, E; Shaw, S; Yoshida, A; Otsuji, S; Murofushi, Y; Aamer, W; Bhat, AA; AlRayahi, J; Al-Shabeeb Akil, AS; Aliyev, E; van Binsbergen, E; Janssen, EJ; Mehrin, KM; Oishi, H; Kobayashi, R; Horii, T; Hatada, I; Saito, A; Hattori, M; Kawano, Y; Lewis, PA; Heesom, KJ; Takarada, T; Sawamoto, K; Matsushita, M; Ogi, T; Butkovic, R; Danson, C; Wilkinson, KA; Fakhro, KA; Zaki, MS; Saitoh, S; Cullen, PJ

SCIENCE TRANSLATIONAL MEDICINE Vol. 17 ( 805 ) page： eadt2426 2025.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Science Translational Medicine

Ritscher-Schinzel syndrome (RSS) is a congenital malformation syndrome characterized by cerebellar, cardiac, and craniofacial malformations and phenotypes associated with liver, skeletal, and kidney dysfunction. The genetic cause of RSS remains to be fully defined, and limited information is available regarding the root cause of the multiple tissue phenotypes. Causative mutations in the Commander multiprotein assembly are an emerging feature of this syndrome. Commander organizes the sorting nexin-17 (SNX17)–dependent recycling of hundreds of integral membrane proteins through the endosomal network. Here, we identify previously unrecognized cohorts of patients with RSS that we genetically and clinically analyzed to identify causative genes in the copper metabolic murr1 domain–containing (COMMD) proteins COMMD4, COMMD9, and coiled-coil domain containing 93 (CCDC93) subunits of the Commander complex. Using interactome analysis, we determined that these mutations disrupted Commander assembly and, through cell surface proteomics, that this reduces tissue-specific presentation of cell surface integral membrane proteins essential for kidney, bone, and brain development. We established that these integral proteins contained ΦxNPxY/F or ΦxNxxY/F sorting motifs in their cytoplasmic-facing domains (where Φ is a hydrophobic residue and x is any residue) that are recognized by SNX17 to drive their Commander-dependent endosomal recycling. Last, through generation of mouse models of RSS, we show replication of RSS-associated clinical phenotypes including proteinuria, skeletal malformation, and neurological impairment. Our data establish RSS as a “recyclinopathy” that arises from a dysfunction in the Commander endosomal recycling pathway.

DOI： 10.1126/scitranslmed.adt2426

De novo CDKN1C variant in Beckwith-Wiedermann spectrum with atypical complications

Moriura, Y; Nishio, Y; Ichimura, S; Noda, H; Tanahashi, Y; Yamamoto, H; Nakazawa, Y; Oso, T; Sato, Y; Takenouchi, T; Saitoh, S; Muramatsu, Y; Ogi, T

HUMAN GENOME VARIATION Vol. 12 ( 1 ) page： 9 2025.5

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

Beckwith–Wiedemann spectrum (BWSp) is a genomic imprinting disorder characterized by a wide range of clinical features. Here we report an infant with BWSp and atypical features, for whom long-read sequencing confirmed a de novo CDKN1C variant that occurred on the maternally inherited allele and excluded other genetic etiologies. These findings not only expand the BWSp concept but also highlight the potential value of allelic origin analysis in cases with atypical presentations.

DOI： 10.1038/s41439-025-00316-0

Paroxysmal Kinesigenic Dyskinesia in Two Siblings With Novel Heterozygous TMEM151A Frameshift Variant: The First Case Report in Japan

Repair mechanisms of endogenous aldehyde-induced DNA damage and associated human disorders Open Access

Oka Yasuyoshi, Ogi Tomoo

Vol. 97 ( 2 ) page： 220 - 224 2025.4

Kurahashi, H; Azuma, Y; Takeuchi, T; Shimada, M; Numoto, S; Nishida, M; Ito, Y; Ogi, T; Okumura, A

AMERICAN JOURNAL OF MEDICAL GENETICS PART A page： e64079 2025.4

Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Medical Genetics, Part A

Paroxysmal kinesigenic dyskinesia is a rare movement disorder that typically has a genetic basis, with PRRT2 being the primary causative gene. However, TMEM151A mutations have recently emerged as causative factors. Here, we report the cases of two Japanese siblings diagnosed with paroxysmal kinesigenic dyskinesia caused by a novel heterozygous TMEM151A frameshift variant (c.760_761insT). Case 1 was a 17-year-old male who had experienced involuntary movements triggered by sudden actions since the age of 12 years. Carbamazepine alleviated the symptoms but caused side effects, leading to a switch to lacosamide, which was effective. Case 2 was a 14-year-old female who experienced subtle discomfort at the onset of physical activity. Genetic analysis confirmed the presence of the same TMEM151A variant in both siblings. Lacosamide effectively managed the patients' symptoms. TMEM151A-positive paroxysmal kinesigenic dyskinesia differs phenotypically from PRRT2-positive paroxysmal kinesigenic dyskinesia, presenting later onset and shorter-duration dystonia. Case 1 presented with dystonia with a relatively long duration of 15 s. We also found differences in involuntary movements among siblings. This report emphasizes the clinical and genetic diversity of paroxysmal kinesigenic dyskinesia, which may lead to challenges in diagnosing sporadic cases, and finally, reports on the efficacy of lacosamide as a treatment.

DOI： 10.1002/ajmg.a.64079

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

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

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

Whole-genome sequencing analysis of Japanese autism spectrum disorder trios

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

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

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

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

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

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

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

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

Yuka Nakazawa, Yasuyoshi Oka, Tomoko Matsunaga, Tomoo Ogi

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

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

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

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

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

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