Genes to cells : devoted to molecular & cellular mechanisms最新文献

Murine Embryonic Stem Cells Possess Distinct E2F Activity That Activates Tumor Suppressor Promoter Elements. 小鼠胚胎干细胞具有独特的激活肿瘤抑制启动子元件的E2F活性。

IF 1.3

Genes to cells : devoted to molecular & cellular mechanisms Pub Date : 2026-05-01 DOI: 10.1111/gtc.70121

Yaxuan Zhou, Rinka Nakajima, Mashiro Shirasawa, Mariana Fikriyanti, Masaru Kitagawa, Thet Yoon San, Ritsuko Iwanaga, Andrew P Bradford, Kenta Kurayoshi, Keigo Araki, Kiyoshi Ohtani

{"title":"Murine Embryonic Stem Cells Possess Distinct E2F Activity That Activates Tumor Suppressor Promoter Elements.","authors":"Yaxuan Zhou, Rinka Nakajima, Mashiro Shirasawa, Mariana Fikriyanti, Masaru Kitagawa, Thet Yoon San, Ritsuko Iwanaga, Andrew P Bradford, Kenta Kurayoshi, Keigo Araki, Kiyoshi Ohtani","doi":"10.1111/gtc.70121","DOIUrl":"10.1111/gtc.70121","url":null,"abstract":"The transcription factor E2F plays crucial roles in cell proliferation and tumor suppression. In the resting state of normal cells, E2F activity is suppressed by binding of the tumor suppressor pRB and its family members. E2F activated by growth stimulation under the control of pRB (physiological E2F) activates growth-related genes and facilitates cell proliferation. In contrast, E2F activated by loss of pRB control, such as forced inactivation of pRB (distinct E2F), activates tumor suppressor genes such as ARF and TAp73 to suppress tumorigenesis. We previously reported that these genes are specifically activated by distinct E2F but not by physiological E2F. In almost all cancers, pRB function is disabled, generating distinct E2F activity, which is tolerated due to concomitant dysfunction of the tumor suppressor p53. Hence, distinct E2F activity is a characteristic feature of cancer cells. Mouse embryonic stem cells (mESCs) proliferate rapidly with shortened gap phases, enhanced cyclin dependent kinase (CDK) activity and hyper-phosphorylated (inactive) pRB. This observation prompted us to examine whether mESCs possess distinct E2F activity. We show here that, like cancer cell lines, mESCs exhibit distinct E2F activity. Moreover, introduction of a small amount of CDK inhibitors enhanced deregulated E2F activity, suggesting that it is suppressed by CDK activity in mESCs.","PeriodicalId":520630,"journal":{"name":"Genes to cells : devoted to molecular & cellular mechanisms","volume":"31 3","pages":"e70121"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147877186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gene Expression Profiles Reveal Altered Metabolic Signaling Pathway in Skeletal Muscle With Lipid Sensor Gpr120/Ffar4 Deficiency. 基因表达谱揭示脂质传感器Gpr120/Ffar4缺乏骨骼肌代谢信号通路改变

IF 1.3

Genes to cells : devoted to molecular & cellular mechanisms Pub Date : 2026-05-01 DOI: 10.1111/gtc.70114

Junfeng Shi, Taito Nakayama, Keiko Iida, Ryohei Shirai, Kenya Ueno, Ayako Hirata, Takeo Awaji, Kei Maruyama, Yuuki Kawamura, Yoshinori Takei, Akira Hirasawa

{"title":"Gene Expression Profiles Reveal Altered Metabolic Signaling Pathway in Skeletal Muscle With Lipid Sensor Gpr120/Ffar4 Deficiency.","authors":"Junfeng Shi, Taito Nakayama, Keiko Iida, Ryohei Shirai, Kenya Ueno, Ayako Hirata, Takeo Awaji, Kei Maruyama, Yuuki Kawamura, Yoshinori Takei, Akira Hirasawa","doi":"10.1111/gtc.70114","DOIUrl":"10.1111/gtc.70114","url":null,"abstract":"Obesity is driven by a chronic imbalance between energy intake and energy expenditure (EE), and reduced EE has been implicated in its development. We previously demonstrated that deficiency of Gpr120/Ffar4, a lipid sensor, led to decreased EE. Since skeletal muscle is a major contributor to EE, we investigated whether Gpr120 is involved in skeletal muscle energy metabolism. We generated gene expression profiles of skeletal muscle in WT mice and Gpr120-deficient (KO) mice under a normal diet (ND) and a high fat diet (HFD) using microarray analysis and found that Gpr120 was associated with mitochondrial gene expression in response to HFD. We also discovered that the enrichment patterns of Gene Ontology (GO) terms in skeletal muscle of Gpr120-deficient mice were common to those of genetically modified mouse models associated with Ampk, Pgc1α, and Errγ, suggesting that these signaling factors may be involved in Gpr120-mediated signaling. Moreover, analyses including ChIP-seq of Errγ, morphological evaluation of mitochondria by electron microscopy, and measurements of mtDNA content and muscle strength demonstrated that Gpr120 was involved in regulating mitochondrial structure, gene expression, and skeletal muscle function. Together, our findings suggest that Gpr120 regulates mitochondrial homeostasis and function in skeletal muscle, possibly through signaling from distant organs.","PeriodicalId":520630,"journal":{"name":"Genes to cells : devoted to molecular & cellular mechanisms","volume":"31 3","pages":"e70114"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147725410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

POU5F1/OCT4 Attenuates Human LINE-1 Expression Levels in Induced Pluripotent Stem Cells. POU5F1/OCT4在诱导多能干细胞中降低人LINE-1表达水平

IF 1.3

Genes to cells : devoted to molecular & cellular mechanisms Pub Date : 2026-05-01 DOI: 10.1111/gtc.70120

Hikaru Suzuki, Kenji Ichiyanagi

{"title":"POU5F1/OCT4 Attenuates Human LINE-1 Expression Levels in Induced Pluripotent Stem Cells.","authors":"Hikaru Suzuki, Kenji Ichiyanagi","doi":"10.1111/gtc.70120","DOIUrl":"10.1111/gtc.70120","url":null,"abstract":"Long interspersed nuclear element-1 (LINE-1, L1) shows high transcriptional activity in human pluripotent stem cells (PSCs). Here, we showed that pluripotency-associated transcription factors (TFs) such as POU5F1 (OCT4), SOX2, KLF4, NANOG, and MYC bind to the 5' untranslated region of full-length L1 copies of young subfamilies (L1HS, L1PA2, L1PA3), with their respective consensus sequences containing their binding motifs. These sites display features of open chromatin, H3K4me3 enrichment, and ATAC-seq signals, suggesting potential transcriptional activation. Notably, knockdown of POU5F1 led to increased L1 expression in independent experiments, suggesting that POU5F1 restricts L1 activity in PSCs. Similar trends were observed for SOX2 and NANOG, although supporting mRNA-seq datasets were limited. ChIP-seq analyses revealed binding of POU5F1, SOX2, NANOG, KLF4, and MYC to the 5' UTR of younger L1 subfamilies. Motif analysis revealed that binding sequences for these TFs are also conserved in older L1 subfamilies, suggesting a role for these TF binding in host fitness and/or L1 amplification. Together, our findings support a model in which pluripotency-associated TFs such as POU5F1 preferentially bind to transcriptionally competent L1 loci and modulate L1 expression in human PSCs, although the extent of their regulatory roles may differ among the TFs.","PeriodicalId":520630,"journal":{"name":"Genes to cells : devoted to molecular & cellular mechanisms","volume":"31 3","pages":"e70120"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147849128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Liver-Specific Deletion of Cnot11 Delays Postnatal Hepatocyte Maturation and Transiently Impairs Liver Function in Mice. 肝脏特异性缺失Cnot11延迟小鼠出生后肝细胞成熟并短暂损害肝功能。

IF 1.3

Genes to cells : devoted to molecular & cellular mechanisms Pub Date : 2026-05-01 DOI: 10.1111/gtc.70117

Saori Nishijima, Toru Suzuki, Takaya Abe, Kana Bando, Tadashi Yamamoto

{"title":"Liver-Specific Deletion of Cnot11 Delays Postnatal Hepatocyte Maturation and Transiently Impairs Liver Function in Mice.","authors":"Saori Nishijima, Toru Suzuki, Takaya Abe, Kana Bando, Tadashi Yamamoto","doi":"10.1111/gtc.70117","DOIUrl":"10.1111/gtc.70117","url":null,"abstract":"The CCR4-NOT complex is a central regulator of post-transcriptional gene expression that controls mRNA deadenylation and decay. Although the catalytic subunits have been well characterized, the physiological roles of several non-catalytic subunits including CNOT11 in mammalian tissues remain incompletely understood. Here, we investigate the physiological role of CNOT11 using genetic mouse models. No homozygous global Cnot11 knockout mice are obtained from heterozygous intercrosses, indicating that CNOT11 is required for early development. We generate hepatocyte-specific Cnot11 knockout mice (Cnot11-LKO) and find that Cnot11-LKO mice exhibit growth retardation and alterations in serum biochemical parameters during early postnatal stages, which are largely resolved by adulthood. Histological analysis does not reveal overt liver injury, while morphological differences in hepatocytes are observed. A marked increase in Ki67-positive cells was observed in the liver of Cnot11-LKO mice relative to control mice. Most Ki67-positive cells express HNF4A, suggesting that hepatocyte maturation is still in progress in the absence of CNOT11. Transcriptomic analyses of early postnatal livers reveal increased expression of cell cycle-related genes and reduced expression of metabolic genes, further supporting delayed liver maturation. These findings suggest that CNOT11 contributes to proper postnatal liver maturation and is required for the timely establishment of metabolically mature hepatocyte functions.","PeriodicalId":520630,"journal":{"name":"Genes to cells : devoted to molecular & cellular mechanisms","volume":"31 3","pages":"e70117"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147795084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Histone Density and Dynamics Shape Mitotic Chromatid Architecture in Xenopus Egg Extracts. 组蛋白密度和动态影响爪蟾卵提取物中有丝分裂染色单体结构。

IF 1.3

Genes to cells : devoted to molecular & cellular mechanisms Pub Date : 2026-05-01 DOI: 10.1111/gtc.70113

Keishi Shintomi, Keita Ohsumi, Mari Iwabuchi, Tatsuya Hirano

{"title":"Histone Density and Dynamics Shape Mitotic Chromatid Architecture in Xenopus Egg Extracts.","authors":"Keishi Shintomi, Keita Ohsumi, Mari Iwabuchi, Tatsuya Hirano","doi":"10.1111/gtc.70113","DOIUrl":"10.1111/gtc.70113","url":null,"abstract":"Mitotic chromosomes, consisting of a pair of rod-shaped chromatids, emerge from a dramatic reorganization of nucleosome fibers. However, the mechanisms by which local chromatin organization influences large-scale mitotic chromatid architecture remain poorly understood. Here, we report a modified cell-free assay in which erythrocyte nuclei, instead of conventionally used sperm nuclei, are incubated in Xenopus mitotic egg extracts. This modification enables mitotic chromatids to assemble from substrates containing regularly spaced, dense nucleosome arrays, allowing chromatid formation to be experimentally separated from nucleosome assembly. In this system, depletion of the linker histone H1.8 results in thinner chromatids with enhanced individualization, whereas excess H1.8 loading promotes chromatid clustering through its C-terminal tail. Chromatid clustering is also observed upon depletion of the histone chaperone Nap1 or the chromatin remodeler ISWI, whose roles have been underappreciated in conventional assays. Together, our findings demonstrate that histone density and dynamics cooperate with condensins and topoisomerase IIα to shape mitotic chromatid architecture.","PeriodicalId":520630,"journal":{"name":"Genes to cells : devoted to molecular & cellular mechanisms","volume":"31 3","pages":"e70113"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13121930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147795108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel Ligands for the Orphan Receptor GPR151 Modulate Morphine Action. 孤儿受体GPR151调节吗啡作用的新配体。

IF 1.3

Genes to cells : devoted to molecular & cellular mechanisms Pub Date : 2026-05-01 DOI: 10.1111/gtc.70119

Hijiri Yoshida, Takashi Suto, Hiroyuki Hirano, Hiroyuki Osada, Kazuto Nunomura, Bangzhong Lin, Shigeru Saito, Shigeki Takeda

{"title":"Novel Ligands for the Orphan Receptor GPR151 Modulate Morphine Action.","authors":"Hijiri Yoshida, Takashi Suto, Hiroyuki Hirano, Hiroyuki Osada, Kazuto Nunomura, Bangzhong Lin, Shigeru Saito, Shigeki Takeda","doi":"10.1111/gtc.70119","DOIUrl":"10.1111/gtc.70119","url":null,"abstract":"GPR151 is an orphan G-protein-coupled receptor expressed on specific neurons. Its expression has been reported to be upregulated in the dorsal root ganglia in mouse nerve injury models, suggesting a role in pain transmission. We used our unique ligand screening system to identify novel agonists and partial agonists for GPR151. The novel ligands, GUM3 and GUM4, have the psoralen ring and exhibited agonist activity (EC50 = 4.1 ± 1.0 μM) and highly weak partial agonist activity (EC50 = 0.81 ± 1.46 μM), respectively, in the [35S]-GTPγS binding assay. Both ligands induced GPR151 internalization and increased reporter gene expression in Chinese hamster ovary cells transiently expressing human GPR151 upon ligand stimulation. Activity evaluation employing structural analogs provided insights into a series of ligand structure-activity relationships. Administration of the unique ligands had no effect on thermal hyperalgesia in rats; however, an agonist and a partial agonist enhanced and attenuated the analgesic effect of morphine, respectively, when co-administered. These findings not only reveal the physiological role of GPR151 in pain transmission but also demonstrate its potential as a novel drug target for pain control. Our findings indicate that the development of GPR151 ligands can contribute to the reduction of opioid use.","PeriodicalId":520630,"journal":{"name":"Genes to cells : devoted to molecular & cellular mechanisms","volume":"31 3","pages":"e70119"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13156533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

EXPRESSION OF CONCERN: Identification of Genes Contributing to Attenuation of Rat Model of Galactose-induced Cataract by Pyruvate. 关注表达：丙酮酸致半乳糖性白内障模型大鼠衰减基因的鉴定。

IF 1.3

Genes to cells : devoted to molecular & cellular mechanisms Pub Date : 2026-05-01 DOI: 10.1111/gtc.70123

引用次数: 0

Comparative Analysis of Closely Related Class XI Myosins Reveals Molecular Determinants of Actin Trajectory Curvature. 密切相关的XI类肌凝蛋白的比较分析揭示了肌动蛋白轨迹曲率的分子决定因素。

IF 1.3

Genes to cells : devoted to molecular & cellular mechanisms Pub Date : 2026-05-01 DOI: 10.1111/gtc.70112

Kohei Yoshimura, Takuma Imi, Taisei Nagai, Takeshi Haraguchi, Kohji Ito

{"title":"Comparative Analysis of Closely Related Class XI Myosins Reveals Molecular Determinants of Actin Trajectory Curvature.","authors":"Kohei Yoshimura, Takuma Imi, Taisei Nagai, Takeshi Haraguchi, Kohji Ito","doi":"10.1111/gtc.70112","DOIUrl":"10.1111/gtc.70112","url":null,"abstract":"Left-right asymmetry in multicellular organisms is often rooted in cellular chirality emerging from asymmetric actin cytoskeleton dynamics. Although several myosins exhibit chiral actin motility in vitro, the molecular determinants regulating actin trajectory curvature remain poorly understood. We found that two closely related class XI myosins from the alga Chara braunii, CbXI-3 and CbXI-4, share ~90% sequence identity yet display strikingly different actin trajectory curvatures, providing a comparative model system. By swapping subdomains between CbXI-3 and CbXI-4, we identified the upper and lower 50-kDa subdomains (U50/L50) as major structural determinants of curvature. Within these, the CM loop in U50 and the HTH loop in L50 are key contributors. Single amino acid substitutions, particularly S388T in the CM loop of CbXI-3, markedly increased curvature, while reciprocal mutations in CbXI-4 partially reversed the phenotype. Combinatorial mutations revealed cooperative effects among multiple residues, indicating curvature is encoded by local interaction networks rather than a single site. Our findings suggest that subtle steric and electrostatic perturbations near the interface generate directional motility. This study provides molecular insight into chiral motor function and establishes a general strategy for identifying motor protein functional diversification.","PeriodicalId":520630,"journal":{"name":"Genes to cells : devoted to molecular & cellular mechanisms","volume":"31 3","pages":"e70112"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147794740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mislocalized Cytosolic Polyphosphate Forms Potentially Toxic Droplets, Highlighting the Essentiality of Vacuolar Polyphosphate in Pi Homeostasis. 错误定位的胞质聚磷酸盐形成潜在的有毒液滴，强调液泡聚磷酸盐在Pi稳态中的重要性。

IF 1.3

Genes to cells : devoted to molecular & cellular mechanisms Pub Date : 2026-05-01 DOI: 10.1111/gtc.70118

Kojiro Takeda, Rumi Okuyama, Hiyori Takechi, Kaho Fujiyama, Machika Hatori, Aoi Miwatari

{"title":"Mislocalized Cytosolic Polyphosphate Forms Potentially Toxic Droplets, Highlighting the Essentiality of Vacuolar Polyphosphate in Pi Homeostasis.","authors":"Kojiro Takeda, Rumi Okuyama, Hiyori Takechi, Kaho Fujiyama, Machika Hatori, Aoi Miwatari","doi":"10.1111/gtc.70118","DOIUrl":"10.1111/gtc.70118","url":null,"abstract":"Inorganic polyphosphate is a phosphate polymer found in nearly all species examined to date. Over decades of research, this biopolymer has been revealed to participate in a broad range of biological phenomena, from phosphate storage to human diseases. Despite these advances, its essential physiological roles that are critical for cellular or organismal survival remain elusive. In the fission yeast Schizosaccharomyces pombe, the vacuolar transporter chaperone (VTC) complex synthesizes polyphosphate within the vacuolar lumen and supports cell viability synergistically with two additional phosphate regulators with the SPX domain, the phosphate sensor: Pqr1, restricting phosphate import, and Xpr1, a phosphate exporter. In this study, we show that the polyphosphate level increases in response to the elevated extracellular Pi concentration or severe phosphate stress upon the loss of both Pqr1 and Xpr1. The VTC complex may alleviate the lethal phosphate stress by polymerizing and sequestering excess phosphates into the vacuoles. Notably, artificial cytoplasmic synthesis of polyphosphate by the bacterial polyphosphate synthase PPK failed to compensate for the essential function of the VTC complex, forming cytoplasmic polyphosphate droplets via liquid-liquid phase separation, which are potentially cytotoxic. These findings highlight the critical importance of spatial regulation of polyphosphate synthesis for its physiological function.","PeriodicalId":520630,"journal":{"name":"Genes to cells : devoted to molecular & cellular mechanisms","volume":"31 3","pages":"e70118"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147725444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacological Correction of Aberrant DSCAML1 Localization by 4-Phenylbutyrate Ameliorates Epileptic Phenotypes in a Mouse Model Harboring the Patient-Specific A2105T Mutation. 4-苯基丁酸对DSCAML1异常定位的药理学纠正改善了具有患者特异性A2105T突变的小鼠模型的癫痫表型

IF 1.3

Genes to cells : devoted to molecular & cellular mechanisms Pub Date : 2026-05-01 DOI: 10.1111/gtc.70115

Yoneko Hayase, Tomoo Owa, Koichi Hashizume, Kyoka Suyama, Tsolmon Bolorbat, Masaki Sone, Yukie Kanno, Ikuko Hasegawa, Satoshi Miyashita, Shinichiro Taya, Mikio Hoshino

{"title":"Pharmacological Correction of Aberrant DSCAML1 Localization by 4-Phenylbutyrate Ameliorates Epileptic Phenotypes in a Mouse Model Harboring the Patient-Specific A2105T Mutation.","authors":"Yoneko Hayase, Tomoo Owa, Koichi Hashizume, Kyoka Suyama, Tsolmon Bolorbat, Masaki Sone, Yukie Kanno, Ikuko Hasegawa, Satoshi Miyashita, Shinichiro Taya, Mikio Hoshino","doi":"10.1111/gtc.70115","DOIUrl":"10.1111/gtc.70115","url":null,"abstract":"DSCAML1 variants are associated with neurodevelopmental disorders and epilepsy. The pathogenic A2105T missense mutation leads to intracellular accumulation of the DSCAML1 protein, preventing its proper localization to the cell surface. Here, we investigated the therapeutic potential of 4-phenylbutyric acid (4PBA), a chemical chaperone, using a patient-derived Dscaml1A2105T/A2105T knock-in mouse model. We demonstrated that 4PBA treatment restores the cell surface localization of the mutant DSCAML1 protein in primary cultured neurons. In the mouse model, oral administration of 4PBA ameliorated key neurodevelopmental deficits, including dendritic retraction in cortical layer V pyramidal neurons and abnormal clustering of somatostatin-positive interneurons in the hippocampus. Furthermore, 4PBA treatment significantly reduced the frequency of epileptic spike-and-wave discharges. These findings suggest that correcting the trafficking defect of DSCAML1 A2105T alleviates downstream neurological symptoms, highlighting the potential of chemical chaperones as a therapeutic strategy for DSCAML1-associated conformational disorders.","PeriodicalId":520630,"journal":{"name":"Genes to cells : devoted to molecular & cellular mechanisms","volume":"31 3","pages":"e70115"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147725465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0