Journal of Molecular Neuroscience最新文献

{"title":"Integrated Bioinformatics and in vivo Validation Identify the MTRNR2L1/MTRNR2L10 Axis as a Candidate Regulator Associated with Cortical NLRP3 Inflammasome-Related Signaling in Experimental Epilepsy","authors":"Hong Gao,&nbsp;Ranze Cai,&nbsp;Qiuping Li,&nbsp;Shuangchen Liu,&nbsp;Xiaojun Zhu","doi":"10.1007/s12031-026-02554-5","DOIUrl":"10.1007/s12031-026-02554-5","url":null,"abstract":"<div><p>The mechanisms underlying seizure-induced cortical injury in status epilepticus-related experimental epilepsy remain incompletely understood, and upstream regulators of inflammasome activation require further clarification. By combining bioinformatics screening with in vivo validation, we examined whether the MTRNR2L1/MTRNR2L10 axis is associated with NLRP3 inflammasome-related signaling in the cerebral cortex of rats subjected to status epilepticus, with the goal of identifying candidate regulators of seizure-induced cortical injury. The GSE134697 dataset was obtained from GEO. Differentially expressed genes (DEGs) were screened using |log2FC|&gt;4 and adjusted <i>P</i> &lt; 0.05. GO/KEGG enrichment analyses, together with a STRING-based protein–protein interaction (PPI) network, prioritized MTRNR2L1/MTRNR2L10 as candidate molecules annotated to the “regulation of signal transduction” pathway for subsequent in vivo validation. Ninety SPF SD rats (10 per group) were used: a basic model module (normal, sham, and EP model) and a target-intervention module (six groups: negative control, overexpression, and knockdown for MTRNR2L1/MTRNR2L10). Behavioral scoring, histopathology, Western blotting, co-immunoprecipitation, and ELISA were performed. Fifty-one DEGs were identified. Among them, only MTRNR2L1/MTRNR2L10 mapped to signal-transduction regulation associated with EP, and their cortical expression in EP rats fell to &lt; 30% of control. Upregulating this axis lowered Racine seizure scores and neurological deficit scores, was associated with reduced NLRP3 inflammasome-related marker expression, mitigated the loss of BBB-related tight-junction protein markers, and reduced cortical neuronal apoptosis. In contrast, silencing either target exacerbated these changes, and co-immunoprecipitation suggested that the two molecules were associated within the same protein complex. The MTRNR2L1/MTRNR2L10 axis may act as a candidate protective regulator in status epilepticus-related experimental epilepsy, in association with reduced NLRP3 inflammasome-related signaling. These findings support further mechanistic evaluation of MTRNR2L1/MTRNR2L10 in seizure-induced cortical injury, but do not establish these molecules as therapeutic targets for drug-resistant epilepsy.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.4,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12031-026-02554-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148248716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploratory Analysis of Neuroimaging and Molecular Findings in a Cohort of Neuronal Ceroid Lipofuscinosis: a Descriptive study","authors":"Elham Rahimian,&nbsp;Majid. R. Tahsini,&nbsp;Mohadeseh Fathi,&nbsp;Sheyda Khalilian,&nbsp;Mohammad Aidin Farahvash,&nbsp;Ali Reza Tavasoli,&nbsp;Golazin Shahbodagh Khan,&nbsp;Mahmoud Reza Ashrafi,&nbsp;Sasan Saket,&nbsp;Mohammad Rahmanian,&nbsp;Mohammad Miryounesi,&nbsp;Soudeh Ghafouri-Fard,&nbsp;Morteza Heidari","doi":"10.1007/s12031-026-02553-6","DOIUrl":"10.1007/s12031-026-02553-6","url":null,"abstract":"<div><p>Neuronal ceroid lipofuscinosis (NCL) is a group of progressive neurodegenerative disorders affecting the brain and retina. This study descriptively characterizes Magnetic Resonance Imaging (MRI) and Proton Magnetic Resonance Spectroscopy (^1H MRS) features across NCL subtypes in 16 patients and preliminarily explores potential associations with clinical severity and genetic findings. Due to the small sample size, no definitive genotype–phenotype correlations could be established; rather, we report observed imaging patterns as hypothesis-generating observations. MRI demonstrated patterns such as thalamic T2-weighted hypointensity and periventricular white matter signal abnormalities, which may reflect disease burden and progression. ^1H MRS, performed in a subset of patients, showed reduced N-Acetyl Aspartate and variable choline peaks. Notably, preliminary subtype-specific metabolic trends were observed across the four subtypes in which MRS was performed, suggesting the potential for metabolite profiling to aid in diagnosis and subtype differentiation. However, these findings are merely exploratory and require validation in larger cohorts. These preliminary findings suggest a complementary role for advanced neuroimaging alongside molecular testing in the early diagnosis and evaluation of NCL, though larger prospective studies are needed to validate these observations.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148222470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A de novo Loss-of-function Variant in RAPGEF6 Supports its Role in Neuropsychiatric Disorders","authors":"Simone Treccarichi,&nbsp;Mirella Vinci,&nbsp;Maria Grazia Figura,&nbsp;Antonino Musumeci,&nbsp;Miriam Virgillito,&nbsp;Carla Papa,&nbsp;Valeria Chiavetta,&nbsp;Desiree Brancato,&nbsp;Francesca Bruno,&nbsp;Concetta Federico,&nbsp;Justin Simo,&nbsp;Roberta La Piana,&nbsp;Salvatore Saccone,&nbsp;Francesco Calì","doi":"10.1007/s12031-026-02557-2","DOIUrl":"10.1007/s12031-026-02557-2","url":null,"abstract":"<div><p><i>RAPGEF6</i> is a member of the guanine nucleotide exchange factor (GEF) subfamily that acts on Rap small GTPases and contains a Ras/Rap-associating domain. Although deficiency of this gene has previously been linked to schizophrenia, no MIM phenotype entry currently associates <i>RAPGEF6</i> with a defined clinical condition. In this study, trio-based whole-exome sequencing (WES) was performed in an individual presenting with psychiatric disorders and mild intellectual disability. WES revealed a de novo frameshift variant, c.272dup (p.Pro92Serfs*6), in the <i>RAPGEF6</i> gene (NM_016340.6). This variant was classified as likely pathogenic according to ACMG criteria. Nonetheless, the contribution of additional genetic factors not detected by WES cannot be excluded. According to developmental transcriptomic data from the BrainSpan database, <i>RAPGEF6</i> is expressed in the human brain across the entire lifespan and participates in neuron projection development, Rap-protein signal transduction, and regulation of GTPase activity. Structural variation data from DECIPHER further indicate that copy-number variants involving <i>RAPGEF6</i> are primarily associated with intellectual disability and micrognathia. In addition, DECIPHER shows that <i>RAPGEF6</i> is highly intolerant to loss-of-function (LoF) variants. Both NMD-Esc predictor and Mutation Taster suggest that the identified frameshift mutation is likely to trigger nonsense-mediated decay (NMD) of the <i>RAPGEF6</i> transcript, resulting in loss of protein production. In addition, RAPGEF6 expression progressively increased during retinoic acid-induced neuronal differentiation of SK-N-BE neuroblastoma cells, supporting a potential role of this gene in neuronal maturation processes. Together, these data support a contributory role of <i>RAPGEF6</i> haploinsufficiency in neurodevelopmental and psychiatric phenotypes, reinforcing its emerging relevance in neuropsychiatric disorders.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12031-026-02557-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148215884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of Umbelliferone Neuroprotective Effects Against Acrylamide-Induced Oxidative Stress, In Vivo and In Silico Study","authors":"Abeer Mogadem,&nbsp;Hanaa H. AL-Refai","doi":"10.1007/s12031-026-02555-4","DOIUrl":"10.1007/s12031-026-02555-4","url":null,"abstract":"<div><p>Acrylamide (ACR) is a heat-generated carcinogen, one of the most common toxins, with various effects on the biological system, including oxidative stress and related disorders. Umbelliferone (UMB) is a naturally occurring coumarin derivative that is present in edible fruits, known as an antioxidant, and reported for many other therapeutic effects. In the current study, UMB was evaluated for neuro- and hepatoprotective activity against oxidative stress toxicity induced by a 40 mg/kg daily dose of ACR in a mouse model over 15 days. Also, UMB was used as a ligand for the first time to predict its affinity for the most important proteins involved in neuronal failure. The UMB administration significantly improves liver enzyme elevations, alanine transaminase (ALT) and aspartate transaminase (AST), following ACR injection. Also, UMB treatment reduced elevated total protein (TP) and albumin (ALB) serum levels. In addition, lipid peroxidation levels were significantly reduced by UMB (expressed as malondialdehyde MDA levels), and the levels of total non-enzymatic antioxidant capacity (TAC) were increased in brain tissue homogenate in comparison with brain injury in the ACR group. Furthermore, UMB downregulated the expression of tumor necrosis factor-alpha (TNF-α), an inflammatory marker and caspase-3, an apoptotic marker, while upregulating heme oxygenase-1 (HO-1), an antioxidant enzyme, in both liver and brain tissues. Molecular docking analysis revealed that the compound could form H-bonds and hydrophobic interactions with the target receptors. Results of this study conclude that UMB may be considered a potential pharmaceutical agent to ameliorate ACR-induced toxicity in the liver and brain, due to its anti-inflammatory, antioxidant, and antiapoptotic mechanisms, as well as its moderate affinity for neuronal disease-targeted proteins.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148209680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking Neuroprotection: Exercise-Induced Muscle Secretome (Myokines) as a Therapeutic Avenue Against Alzheimer’s Disease Pathogenesis","authors":"Hossein Shirvani,&nbsp;Linda S. Pescatello,&nbsp;Ali Reza Eftekhari Moghadam,&nbsp;Ehsan Arabzadeh","doi":"10.1007/s12031-026-02556-3","DOIUrl":"10.1007/s12031-026-02556-3","url":null,"abstract":"<div><p>This review critically evaluates exercise-induced myokines as neuroprotective agents against Alzheimer’s disease (AD) and is structured around three thematic sections: (1) mechanistic foundations of myokine neuroprotection, (2) translational barriers to therapeutic development, and (3) a strategic framework for future research. Epidemiological studies associate physical exercise with reduced AD risk (30–45%), yet mechanisms remain incompletely resolved. Preclinical studies demonstrate that exercise-induced myokines (Irisin, BDNF, Cathepsin B) modulate AD pathology by: (1) attenuating amyloid-beta (Aβ)/tau accumulation, (2) suppressing neuroinflammation, and (3) enhancing synaptic plasticity. However, human exercise interventions show conflicting results influenced by APOE genotype, age, and exercise modality. Associative human data suggest that Interleukin-6 (IL-6) exemplifies pleiotropy—affording neuroprotective effects in acute contexts but potentially detrimental effects in states of chronic inflammation. Therapeutic hurdles include blood-brain barrier (BBB) penetration, pleiotropic risks, and patient heterogeneity. Emerging concepts such as combinatorial approaches (nanocarriers, exercise mimetics) and biomarker-driven trials are proposed as hypothetical future strategies; however, these remain unvalidated and require substantial preclinical development before implemented in clinical care. This narrative review is structured around three thematic sections: mechanistic foundations of myokine neuroprotection, translational barriers to therapeutic development, and a strategic framework for future research. The muscle-brain axis represents a compelling but complex therapeutic target. Based on current preclinical and correlational human evidence, future research should prioritize mechanistic rigor, standardized biomarker validation, and clinically viable delivery strategies. Notably, several approaches discussed herein—including nanocarrier delivery systems, exercise mimetics, and combinatorial myokine cocktails—remain speculative and are presented as future research directions rather than established therapeutic interventions.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148209684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating Molecular Pathology, Tumor Microenvironment, and Novel Therapies to Overcome Resistance in Glioblastoma","authors":"Smita Kumari,&nbsp;Jyotsna Misra,&nbsp;Karthikeyan Ravi,&nbsp;Naveen Kumar,&nbsp;Niraj Kumar Jha,&nbsp;Rohan Gupta","doi":"10.1007/s12031-026-02536-7","DOIUrl":"10.1007/s12031-026-02536-7","url":null,"abstract":"<div><p>Glioblastoma multiforme (GBM) represents the most aggressive primary brain tumor in adults, characterized by significant heterogeneity, rapid progression, and resistance to existing therapies. Conventional therapies provide minimal survival advantages due to recurrence influenced by glioma stem-like cells (GSCs), adaptive signaling pathways, and a highly immunosuppressive tumor microenvironment (TME). Further, molecular profiling has revealed significant alterations, including EGFR amplification, IDH mutations, MGMT promoter methylation, and TERT promoter changes; however, challenges persist in the integration of genomic, epigenetic, metabolic, and transcriptomic data for the development of effective therapies. Thus, this review examines the limitations by integrating recent developments in molecular classification, dysregulated signaling pathways, metabolic reprogramming, and non-coding RNA-mediated regulation in GBM. Additionally, the manuscript emphasizes novel therapeutic strategies, such as nanomedicine, oncolytic virotherapy, immunotherapy, tumor-treating fields, and phytochemical-based interventions, as well as the increasing significance of artificial intelligence and machine learning in diagnosis and personalized treatment. Lastly, this review integrates mechanistic and translational insights to establish a framework addressing blood–brain barrier limitations, therapeutic resistance, and immune evasion, thereby facilitating the advancement of precision medicine approaches for enhanced GBM outcomes.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shared Immunogenetic Basis Between Spleen Volume and Psychiatric Disorders","authors":"Fang Liang,&nbsp;Wenxuan Zhao,&nbsp;Fan Ning,&nbsp;Yajun Yun,&nbsp;Jiaqi Song,&nbsp;Ting Ma,&nbsp;Qi Zhang","doi":"10.1007/s12031-026-02550-9","DOIUrl":"10.1007/s12031-026-02550-9","url":null,"abstract":"<div><p>Psychiatric disorders are closely linked to immune dysregulation, yet the genetic relationships between peripheral immune organs, particularly the spleen, and different psychiatric disorders remain poorly understood. This study aimed to explore these associations. Linkage disequilibrium score regression (LDSC) was used to evaluate the genetic correlations between spleen volume and schizophrenia, bipolar disorder, and depression. For the two traits showing significant genetic correlation, MAGMA gene-level analysis was further performed to identify significant overlapping genes as shared genes. KEGG and GO enrichment analyses were then conducted for these shared genes. In addition, a protein–protein interaction (PPI) network was constructed based on the STRING database, and hub genes were identified using the CytoHubba plugin in Cytoscape. Meanwhile, cell-type enrichment analysis was performed using single-cell transcriptomic reference datasets from the human cortex, hippocampus, and midbrain to localize the potential cellular context underlying the relevant genetic signals. To further investigate the potential functional genomic effects of spleen volume-associated genetic signals in depression-relevant brain regions, transcriptome-wide association study (TWAS) analyses were performed for spleen volume in the human prefrontal cortex and hippocampus. Functional enrichment analyses were subsequently conducted for the overlapping TWAS-associated genes identified in these two regions. Among the three major psychiatric disorders, only depression showed a significant genetic correlation with spleen volume. Spleen volume and depression shared 25 genes, which were mainly enriched in immune- and inflammation-related pathways, including antigen processing and presentation, natural killer cell-mediated cytotoxicity, NF-κB signaling, MAPK signaling, phagosome, and lysosome biogenesis. PPI network analysis further identified several hub genes closely related to immune regulation. Single-cell analysis revealed that the relevant genetic signals were significantly enriched in microglia across the cortex, hippocampus, and midbrain. Additional TWAS analyses in the prefrontal cortex and hippocampus identified 19 overlapping spleen volume-associated transcriptomic genes, with enrichment in immune-inflammatory regulation, monoamine neurotransmitter metabolism, apoptosis, and tryptophan metabolism-related pathways. Spleen volume and depression may share an immunoinflammatory genetic basis and may be linked through microglia-mediated central immune mechanisms, providing new genetic evidence for understanding spleen–brain axis interactions in depression.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148100749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biochemical Predictors in the Blood Serum of Children with TORCH Encephalopathy and Autism","authors":"Nodirakhon Khusenova,&nbsp;Yakuthon Madjidova,&nbsp;Shukhrat Usmanov,&nbsp;Latofat Ziyakhodjaeva,&nbsp;Gulnora Rixsiyeva,&nbsp;Rano Yunusova,&nbsp;Taj Mohammad","doi":"10.1007/s12031-026-02551-8","DOIUrl":"10.1007/s12031-026-02551-8","url":null,"abstract":"<div><p>TORCH-associated encephalopathy in children with autism spectrum disorder (ASD) is accompanied by a pronounced neurometabolic syndrome characterized by neuronal damage, mitochondrial energy deficiency, and disturbances in methylation processes. In the present study, children with ASD and confirmed TORCH-related central nervous system injury demonstrated significantly elevated serum levels of neuron-specific enolase (NSE), lactate, ammonia, and homocysteine, reflecting neuronal injury, mitochondrial dysfunction, and metabolic dysregulation. These alterations were more pronounced than in children with idiopathic autism and in healthy controls, suggesting a possible contribution of infection-related neuroinflammatory mechanisms to ASD pathology. The combined assessment of NSE, lactate, ammonia, and homocysteine represents a biologically relevant set of biochemical predictors for TORCH-induced encephalopathy in children with ASD. Elevated levels of these markers were closely associated with the severity of cognitive, emotional, and adaptive impairments, as well as with more severe clinical forms of autism. Thus, an integrated biochemical profiling approach may serve as a valuable basis for early risk stratification, differential diagnosis, and the development of personalized metabolic and neuroprotective therapeutic strategies in children with autism associated with TORCH infections.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Susceptibility to Autism Spectrum Disorders: Folate Pathway Polymorphisms, Mediterranean Diet and Evolutionary Insights","authors":"Maria Addolorata Bonifacio,&nbsp;Angela Vinella,&nbsp;Mariella Pafundi,&nbsp;Lucia Margari,&nbsp;Maria Addolorata Mariggiò","doi":"10.1007/s12031-026-02552-7","DOIUrl":"10.1007/s12031-026-02552-7","url":null,"abstract":"<div><p>Autism spectrum disorders (ASD) represent a complex medical and social issue with a multifactorial etiology, often correlated with the host genetic background, particularly with the folate metabolic pathway. This study aimed to investigate the association between MTHFR (C677T and A1298C) and MTRR (A66G) polymorphisms and ASD susceptibility in an Apulian cohort. We analyzed 73 patients diagnosed with ASD and 84 healthy controls recruited at the University Hospital Policlinico, Bari. Genotyping was performed using a Real-time/FRET method. Statistical analysis evaluated genotypic/allelic distributions and haplotype frequencies. While single genotype distributions did not differ significantly between groups, the MTHFR 677T allele frequency was significantly higher in controls (50%) compared to the ASD group (37.67%; <i>p</i> = 0.038), suggesting a potential protective role. Haplotype analysis identified the C-C-G combination as a significant risk factor for ASD (OR = 3.60; <i>p</i> = 0.019). In silico analysis confirmed that the C677T polymorphism (A222V) significantly destabilizes the MTHFR protein structure, in agreement with previous findings. Our findings suggest that an unknown evolutionary advantage may explain the circulation of the MTHFR 677T allele in the general Apulian population, supported by the high folate intake peculiar to the Mediterranean diet. The enzymatic alterations caused by the C-C-G haplotype, selected by the ASD Apulian group, are herein detrimental for folate metabolism.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MECP2 Variant Spectrum and Genotype–Phenotype Correlations in Iranian Rett Syndrome Patients: Identification of a Novel Frameshift Mutation","authors":"Parnoush Booalizadeh,&nbsp;Iman Salahshourifar,&nbsp;Bahareh Rabbani,&nbsp;Morteza Rezvani,&nbsp;Mahmoud Reza Ashrafi,&nbsp;Nejat Mahdieh","doi":"10.1007/s12031-026-02545-6","DOIUrl":"10.1007/s12031-026-02545-6","url":null,"abstract":"<div><p>Background rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder primarily affecting females, predominantly caused by pathogenic variants in the MECP2 gene. This study investigates the genetic and phenotypic spectrum of RTT in Iran, a population characterized by high genetic diversity and consanguinity. Methods twenty-five Iranian RTT patients (24 females, 1 male; aged 2–17 years), including 11 newly diagnosed and 14 previously reported cases, were analyzed. Clinical evaluation, pedigree analysis, and bidirectional sequencing of all MECP2 coding exons (NM_004992.3) were performed. Variant pathogenicity was assessed using ACMG criteria and in silico tools (MutationTaster, VarSome, Franklin). Structural impact of the novel variant was modeled using RoseTTAFold. Results a novel frameshift variant, c.1268_1269insGGGCACTC; p. Leu424GlyfsTer61, was identified in exon 4 and classified as likely pathogenic. Fifteen distinct MECP2 variants were detected, with 87% pathogenic/likely pathogenic; exon 4 emerged as a mutational hotspot. All patients showed psychomotor regression, loss of purposeful hand use, and communication impairment. Common features included locomotion difficulties (96%), microcephaly (64%), seizures (60%), and abnormal EEG (64%). Truncating variants (nonsense/frameshift) correlated with severe phenotypes (e.g., quadriplegia, feeding difficulties), though statistical significance was limited by sample size (Fisher’s exact test, p = 1.00). Conclusions this study reveals a distinct MECP2 mutation profile in Iranian RTT patients, including a novel pathogenic variant, and highlights genotype–phenotype associations influenced by regional genetic factors. Targeted MECP2 exon 4 sequencing is recommended for efficient diagnosis. These findings support the development of personalized diagnostic and therapeutic approaches in high-consanguinity populations and lay the foundation for future genomic and functional studies in Iran.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}