Pub Date : 2024-07-08DOI: 10.1007/s10048-024-00772-w
Yang Xu, XiaoDan Teng, Ming Wei, Yang Liu
Our objective is to explore the protective effect of Dexmedetomidine on brain apoptosis and its mechanism through TREK-1 pathway. Forty male Sprague-Dawley rats were allocated into four groups: Sham, Cerebral Ischemia/Reperfusion Injury (CIRI), 50 µg/kg Dex, and 100 µg/kg Dex. A rat model of middle cerebral artery occlusion (MCAO) was employed to simulate cerebral embolism. Primary cortical neurons were exposed to Dex for 48 h, with some receiving additional treatment with 100 µM yohimbine hydrochloride (YOH) or TREK-1 small interfering RNA (siRNA). Neuronal damage was assessed using hematoxylin and eosin (HE) staining. Cell viability and apoptosis were measured by Cell Counting Kit-8 (CCK8) and flow cytometry, respectively. Protein and gene expression levels of Bcl-2, Bax, and TREK-1 were determined by Western blot and real-time polymerase chain reaction (PCR). Histopathological changes revealed that Dex treatment at both 50 µg/kg and 100 µg/kg significantly mitigated neuronal damage compared to the CIRI group. YOH treatment and Trek1 siRNA significantly reduced cell viability (p < 0.05). The mRNA expression and protein levels of TREK-1 and Bax were remarkably increased, while mRNA expression and protein levels of Bcl-2 was seriously decreased after CIRI modeling. In contrast, Dex treatment at both concentrations led to decreased TREK-1 and Bax expression and increased Bcl-2 expression in primary cortical neurons. Addition of 100 µM YOH and Trek1 siRNA reversed the effects of Dex on apoptosis-related genes (p < 0.05). Dex exerts neuroprotective effects through the TREK-1 pathway in vivo and in vitro.
{"title":"TREK-1 channel as a therapeutic target for dexmedetomidine-mediated neuroprotection in cerebral ischemia.","authors":"Yang Xu, XiaoDan Teng, Ming Wei, Yang Liu","doi":"10.1007/s10048-024-00772-w","DOIUrl":"https://doi.org/10.1007/s10048-024-00772-w","url":null,"abstract":"<p><p>Our objective is to explore the protective effect of Dexmedetomidine on brain apoptosis and its mechanism through TREK-1 pathway. Forty male Sprague-Dawley rats were allocated into four groups: Sham, Cerebral Ischemia/Reperfusion Injury (CIRI), 50 µg/kg Dex, and 100 µg/kg Dex. A rat model of middle cerebral artery occlusion (MCAO) was employed to simulate cerebral embolism. Primary cortical neurons were exposed to Dex for 48 h, with some receiving additional treatment with 100 µM yohimbine hydrochloride (YOH) or TREK-1 small interfering RNA (siRNA). Neuronal damage was assessed using hematoxylin and eosin (HE) staining. Cell viability and apoptosis were measured by Cell Counting Kit-8 (CCK8) and flow cytometry, respectively. Protein and gene expression levels of Bcl-2, Bax, and TREK-1 were determined by Western blot and real-time polymerase chain reaction (PCR). Histopathological changes revealed that Dex treatment at both 50 µg/kg and 100 µg/kg significantly mitigated neuronal damage compared to the CIRI group. YOH treatment and Trek1 siRNA significantly reduced cell viability (p < 0.05). The mRNA expression and protein levels of TREK-1 and Bax were remarkably increased, while mRNA expression and protein levels of Bcl-2 was seriously decreased after CIRI modeling. In contrast, Dex treatment at both concentrations led to decreased TREK-1 and Bax expression and increased Bcl-2 expression in primary cortical neurons. Addition of 100 µM YOH and Trek1 siRNA reversed the effects of Dex on apoptosis-related genes (p < 0.05). Dex exerts neuroprotective effects through the TREK-1 pathway in vivo and in vitro.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141556070","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}
Pub Date : 2024-07-05DOI: 10.1007/s10048-024-00771-x
Jan Postberg, Michèle Tina Schubert, Vincent Nin, Lukas Wagner, Martina Piefke
The debate surrounding nature versus nurture remains a central question in neuroscience, psychology, and in psychiatry, holding implications for both aging processes and the etiology of mental illness. Epigenetics can serve as a bridge between genetic predisposition and environmental influences, thus offering a potential avenue for addressing these questions. Epigenetic clocks, in particular, offer a theoretical framework for measuring biological age based on DNA methylation signatures, enabling the identification of disparities between biological and chronological age. This structured review seeks to consolidate current knowledge regarding the relationship between mental disorders and epigenetic age within the brain. Through a comprehensive literature search encompassing databases such as EBSCO, PubMed, and ClinicalTrials.gov, relevant studies were identified and analyzed. Studies that met inclusion criteria were scrutinized, focusing on those with large sample sizes, analyses of both brain tissue and blood samples, investigation of frontal cortex markers, and a specific emphasis on schizophrenia and depressive disorders. Our review revealed a paucity of significant findings, yet notable insights emerged from studies meeting specific criteria. Studies characterized by extensive sample sizes, analysis of brain tissue and blood samples, assessment of frontal cortex markers, and a focus on schizophrenia and depressive disorders yielded particularly noteworthy results. Despite the limited number of significant findings, these studies shed light on the complex interplay between epigenetic aging and mental illness. While the current body of literature on epigenetic aging in mental disorders presents limited significant findings, it underscores the importance of further research in this area. Future studies should prioritize large sample sizes, comprehensive analyses of brain tissue and blood samples, exploration of specific brain regions such as the frontal cortex, and a focus on key mental disorders. Such endeavors will contribute to a deeper understanding of the relationship between epigenetic aging and mental illness, potentially informing novel diagnostic and therapeutic approaches.
围绕天性与后天培养的争论仍然是神经科学、心理学和精神病学的核心问题,对衰老过程和精神疾病的病因学都有影响。表观遗传学可以在遗传易感性和环境影响之间架起一座桥梁,从而为解决这些问题提供一条潜在的途径。表观遗传学时钟尤其提供了一个理论框架,可根据 DNA 甲基化特征来测量生物年龄,从而识别生物年龄与计时年龄之间的差异。本结构性综述旨在整合当前有关精神障碍与大脑表观遗传年龄之间关系的知识。通过对 EBSCO、PubMed 和 ClinicalTrials.gov 等数据库进行全面的文献检索,确定并分析了相关研究。我们对符合纳入标准的研究进行了仔细审查,重点关注那些样本量大、同时分析脑组织和血液样本、调查额叶皮层标记物以及特别强调精神分裂症和抑郁障碍的研究。我们的综述显示,重大发现并不多,但在符合特定标准的研究中却出现了值得注意的见解。这些研究的特点是样本量大、分析脑组织和血液样本、评估额叶皮层标记物,而且重点关注精神分裂症和抑郁障碍,这些研究的结果尤其值得关注。尽管重要发现的数量有限,但这些研究揭示了表观遗传衰老与精神疾病之间复杂的相互作用。虽然目前有关精神疾病表观遗传衰老的文献中的重要发现有限,但它强调了在这一领域开展进一步研究的重要性。未来的研究应优先考虑大样本量、对脑组织和血液样本进行全面分析、对额叶皮层等特定脑区进行探索,并重点关注主要的精神疾病。这些努力将有助于更深入地了解表观遗传衰老与精神疾病之间的关系,并有可能为新的诊断和治疗方法提供依据。
{"title":"A perspective on epigenomic aging processes in the human brain and their plasticity in patients with mental disorders - a systematic review.","authors":"Jan Postberg, Michèle Tina Schubert, Vincent Nin, Lukas Wagner, Martina Piefke","doi":"10.1007/s10048-024-00771-x","DOIUrl":"https://doi.org/10.1007/s10048-024-00771-x","url":null,"abstract":"<p><p>The debate surrounding nature versus nurture remains a central question in neuroscience, psychology, and in psychiatry, holding implications for both aging processes and the etiology of mental illness. Epigenetics can serve as a bridge between genetic predisposition and environmental influences, thus offering a potential avenue for addressing these questions. Epigenetic clocks, in particular, offer a theoretical framework for measuring biological age based on DNA methylation signatures, enabling the identification of disparities between biological and chronological age. This structured review seeks to consolidate current knowledge regarding the relationship between mental disorders and epigenetic age within the brain. Through a comprehensive literature search encompassing databases such as EBSCO, PubMed, and ClinicalTrials.gov, relevant studies were identified and analyzed. Studies that met inclusion criteria were scrutinized, focusing on those with large sample sizes, analyses of both brain tissue and blood samples, investigation of frontal cortex markers, and a specific emphasis on schizophrenia and depressive disorders. Our review revealed a paucity of significant findings, yet notable insights emerged from studies meeting specific criteria. Studies characterized by extensive sample sizes, analysis of brain tissue and blood samples, assessment of frontal cortex markers, and a focus on schizophrenia and depressive disorders yielded particularly noteworthy results. Despite the limited number of significant findings, these studies shed light on the complex interplay between epigenetic aging and mental illness. While the current body of literature on epigenetic aging in mental disorders presents limited significant findings, it underscores the importance of further research in this area. Future studies should prioritize large sample sizes, comprehensive analyses of brain tissue and blood samples, exploration of specific brain regions such as the frontal cortex, and a focus on key mental disorders. Such endeavors will contribute to a deeper understanding of the relationship between epigenetic aging and mental illness, potentially informing novel diagnostic and therapeutic approaches.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141536070","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}
Pub Date : 2024-07-03DOI: 10.1007/s10048-024-00769-5
Hong Cheng, Yingjie Zhao, Xiaoli Hou, Fang Ling, Jing Wang, Yixia Wang, Yasen Cao
Glioma, a type of brain tumor, poses significant challenges due to its heterogeneous nature and limited treatment options. Interferon-related genes (IRGs) have emerged as potential players in glioma pathogenesis, yet their expression patterns and clinical implications remain to be fully elucidated. We conducted a comprehensive analysis to investigate the expression patterns and functional enrichment of IRGs in glioma. This involved constructing protein-protein interaction networks, heatmap analysis, survival curve plotting, diagnostic and prognostic assessments, differential expression analysis across glioma subgroups, GSVA, immune infiltration analysis, and drug sensitivity analysis. Our analysis revealed distinct expression patterns and functional enrichment of IRGs in glioma. Notably, IFNW1 and IFNA21 were markedly downregulated in glioma tissues compared to normal tissues, and higher expression levels were associated with improved overall survival and disease-specific survival. Furthermore, these genes showed diagnostic capabilities in distinguishing glioma tissues from normal tissues and were significantly downregulated in higher-grade and more aggressive gliomas. Differential expression analysis across glioma subgroups highlighted the association of IFNW1 and IFNA21 expression with key pathways and biological processes, including metabolic reprogramming and immune regulation. Immune infiltration analysis revealed their influence on immune cell composition in the tumor microenvironment. Additionally, elevated expression levels were associated with increased resistance to chemotherapeutic agents. Our findings underscore the potential of IFNW1 and IFNA21 as diagnostic biomarkers and prognostic indicators in glioma. Their roles in modulating glioma progression, immune response, and drug sensitivity highlight their significance as potential therapeutic targets. These results contribute to a deeper understanding of glioma biology and may inform the development of personalized treatment strategies for glioma patients.
{"title":"Unveiling the therapeutic prospects of IFNW1 and IFNA21: insights into glioma pathogenesis and clinical significance.","authors":"Hong Cheng, Yingjie Zhao, Xiaoli Hou, Fang Ling, Jing Wang, Yixia Wang, Yasen Cao","doi":"10.1007/s10048-024-00769-5","DOIUrl":"https://doi.org/10.1007/s10048-024-00769-5","url":null,"abstract":"<p><p>Glioma, a type of brain tumor, poses significant challenges due to its heterogeneous nature and limited treatment options. Interferon-related genes (IRGs) have emerged as potential players in glioma pathogenesis, yet their expression patterns and clinical implications remain to be fully elucidated. We conducted a comprehensive analysis to investigate the expression patterns and functional enrichment of IRGs in glioma. This involved constructing protein-protein interaction networks, heatmap analysis, survival curve plotting, diagnostic and prognostic assessments, differential expression analysis across glioma subgroups, GSVA, immune infiltration analysis, and drug sensitivity analysis. Our analysis revealed distinct expression patterns and functional enrichment of IRGs in glioma. Notably, IFNW1 and IFNA21 were markedly downregulated in glioma tissues compared to normal tissues, and higher expression levels were associated with improved overall survival and disease-specific survival. Furthermore, these genes showed diagnostic capabilities in distinguishing glioma tissues from normal tissues and were significantly downregulated in higher-grade and more aggressive gliomas. Differential expression analysis across glioma subgroups highlighted the association of IFNW1 and IFNA21 expression with key pathways and biological processes, including metabolic reprogramming and immune regulation. Immune infiltration analysis revealed their influence on immune cell composition in the tumor microenvironment. Additionally, elevated expression levels were associated with increased resistance to chemotherapeutic agents. Our findings underscore the potential of IFNW1 and IFNA21 as diagnostic biomarkers and prognostic indicators in glioma. Their roles in modulating glioma progression, immune response, and drug sensitivity highlight their significance as potential therapeutic targets. These results contribute to a deeper understanding of glioma biology and may inform the development of personalized treatment strategies for glioma patients.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494418","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}
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive allelic muscle diseases caused by dystrophin gene mutations. Eight hundred thirty-seven patients admitted between 1997 and 2022 were included in the study. Two hundred twenty patients were analyzed by multiplex PCR (mPCR) alone. Five hundred ninety-five patients were investigated by multiplex ligation-dependent probe amplification (MLPA), and 54 patients were examined by sequencing. Deletion was detected in 60% (132/220) of the cases in the mPCR group only and in 58.3% (347/595) of the cases with MLPA analysis. The rates of deletion and duplication were 87.7% and 12.3%, respectively, in the MLPA analysis. Single exon deletions were the most common mutation type. The introns 43-55 (81.8%) and exons 2-21 (13.1%) regions were detected as hot spots in deletions. It was determined that 89% of the mutations were suitable for exon skipping therapy. The reading frame rule did not hold in 7.6% of D/BMD cases (17/224). We detected twenty-five pathogenic/likely pathogenic variants in sequencing, five of which were novel variants. Nonsense mutation was the most common small mutation (44%). 21% of DMD patients were familial. We detected germline mosaicism in four families (4.3%) in the large rearrangement group and one gonosomal mosaicism in a family with a nonsense mutation. This is the largest study examining genotype and phenotype data in Turkish D/BMD families investigated by MLPA analysis. The reading frame hypothesis is not valid in all cases. Sharing the genotype and phenotype characteristics of these cases in the literature will shed light on the molecular structure of DMD and guide gene therapy research. In genetic counseling, carrier screening in the family and possible gonadal mosaicism should be emphasized.
{"title":"Investigation of genotype-phenotype and familial features of Turkish dystrophinopathy patients.","authors":"Hande Ozkalayci, Elcin Bora, Tufan Cankaya, Mehmet Kocabey, Nadide Cemre Zubari, Uluc Yis, Ozlem Giray Bozkaya, Serkan Turan, Aynur Pekcanlar Akay, Ahmet Okay Caglayan, Ayfer Ulgenalp","doi":"10.1007/s10048-024-00765-9","DOIUrl":"10.1007/s10048-024-00765-9","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive allelic muscle diseases caused by dystrophin gene mutations. Eight hundred thirty-seven patients admitted between 1997 and 2022 were included in the study. Two hundred twenty patients were analyzed by multiplex PCR (mPCR) alone. Five hundred ninety-five patients were investigated by multiplex ligation-dependent probe amplification (MLPA), and 54 patients were examined by sequencing. Deletion was detected in 60% (132/220) of the cases in the mPCR group only and in 58.3% (347/595) of the cases with MLPA analysis. The rates of deletion and duplication were 87.7% and 12.3%, respectively, in the MLPA analysis. Single exon deletions were the most common mutation type. The introns 43-55 (81.8%) and exons 2-21 (13.1%) regions were detected as hot spots in deletions. It was determined that 89% of the mutations were suitable for exon skipping therapy. The reading frame rule did not hold in 7.6% of D/BMD cases (17/224). We detected twenty-five pathogenic/likely pathogenic variants in sequencing, five of which were novel variants. Nonsense mutation was the most common small mutation (44%). 21% of DMD patients were familial. We detected germline mosaicism in four families (4.3%) in the large rearrangement group and one gonosomal mosaicism in a family with a nonsense mutation. This is the largest study examining genotype and phenotype data in Turkish D/BMD families investigated by MLPA analysis. The reading frame hypothesis is not valid in all cases. Sharing the genotype and phenotype characteristics of these cases in the literature will shed light on the molecular structure of DMD and guide gene therapy research. In genetic counseling, carrier screening in the family and possible gonadal mosaicism should be emphasized.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293942","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}
Pub Date : 2024-07-01Epub Date: 2024-06-07DOI: 10.1007/s10048-024-00766-8
Elka Stefanova, Ana Marjanović, Valerija Dobričić, Gorana Mandić-Stojmenović, Tanja Stojković, Marija Branković, Maksim Šarčević, Ivana Novaković, Vladimir S Kostić
Most of the heritability in frontotemporal dementia (FTD) is accounted for by autosomal dominant hexanucleotide expansion in the chromosome 9 open reading frame 72 (C9orf72), pathogenic/likely pathogenic variants in progranulin (GRN), and microtubule-associated protein tau (MAPT) genes. Until now, there has been no systematic analysis of these genes in the Serbian population. Herein, we assessed the frequency of the C9orf72 expansion, pathogenic/likely pathogenic variants in GRN and MAPT in a well-characterized group of 472 subjects (FTD, Alzheimer's disease - AD, mild cognitive impairment - MCI, and unspecified dementia - UnD), recruited in the Memory Center, Neurology Clinic, University Clinical Center of Serbia. The C9orf72 repeat expansion was detected in 6.98% of FTD cases (13.46% familial; 2.6% sporadic). In the UnD subgroup, C9orf72 repeat expansions were detected in 4.08% (8% familial) individuals. Pathogenic variants in the GRN were found in 2.85% of familial FTD cases. Interestingly, no MAPT pathogenic/likely pathogenic variants were detected, suggesting possible geographical specificity. Our findings highlight the importance of wider implementation of genetic testing in neurological and psychiatric practice managing patients with cognitive-behavioral and motor symptoms.
{"title":"Frequency of C9orf72, GRN, and MAPT pathogenic variants in patients recruited at the Belgrade Memory Center.","authors":"Elka Stefanova, Ana Marjanović, Valerija Dobričić, Gorana Mandić-Stojmenović, Tanja Stojković, Marija Branković, Maksim Šarčević, Ivana Novaković, Vladimir S Kostić","doi":"10.1007/s10048-024-00766-8","DOIUrl":"10.1007/s10048-024-00766-8","url":null,"abstract":"<p><p>Most of the heritability in frontotemporal dementia (FTD) is accounted for by autosomal dominant hexanucleotide expansion in the chromosome 9 open reading frame 72 (C9orf72), pathogenic/likely pathogenic variants in progranulin (GRN), and microtubule-associated protein tau (MAPT) genes. Until now, there has been no systematic analysis of these genes in the Serbian population. Herein, we assessed the frequency of the C9orf72 expansion, pathogenic/likely pathogenic variants in GRN and MAPT in a well-characterized group of 472 subjects (FTD, Alzheimer's disease - AD, mild cognitive impairment - MCI, and unspecified dementia - UnD), recruited in the Memory Center, Neurology Clinic, University Clinical Center of Serbia. The C9orf72 repeat expansion was detected in 6.98% of FTD cases (13.46% familial; 2.6% sporadic). In the UnD subgroup, C9orf72 repeat expansions were detected in 4.08% (8% familial) individuals. Pathogenic variants in the GRN were found in 2.85% of familial FTD cases. Interestingly, no MAPT pathogenic/likely pathogenic variants were detected, suggesting possible geographical specificity. Our findings highlight the importance of wider implementation of genetic testing in neurological and psychiatric practice managing patients with cognitive-behavioral and motor symptoms.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141285402","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}
Pub Date : 2024-07-01Epub Date: 2024-03-19DOI: 10.1007/s10048-024-00755-x
Marija Brankovic, Vukan Ivanovic, Ivana Basta, Rin Khang, Eugene Lee, Zorica Stevic, Branislav Ralic, Radoje Tubic, GoHun Seo, Vladana Markovic, Ivo Bozovic, Marina Svetel, Ana Marjanovic, Nikola Veselinovic, Sarlota Mesaros, Milena Jankovic, Dusanka Savic-Pavicevic, Zita Jovin, Ivana Novakovic, Hane Lee, Stojan Peric
Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases with a high genetic and clinical heterogeneity. Numerous HSP patients remain genetically undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel variants and genes is needed. Our previous study analyzed 74 adult Serbian HSP patients from 65 families using panel of the 13 most common HSP genes in combination with a copy number variation analysis. Conclusive genetic findings were established in 23 patients from 19 families (29%). In the present study, nine patients from nine families previously negative on the HSP gene panel were selected for the whole exome sequencing (WES). Further, 44 newly diagnosed adult HSP patients from 44 families were sent to WES directly, since many studies showed WES may be used as the first step in HSP diagnosis. WES analysis of cohort 1 revealed a likely genetic cause in five (56%) of nine HSP families, including variants in the ETHE1, ZFYVE26, RNF170, CAPN1, and WASHC5 genes. In cohort 2, possible causative variants were found in seven (16%) of 44 patients (later updated to 27% when other diagnosis were excluded), comprising six different genes: SPAST, SPG11, WASCH5, KIF1A, KIF5A, and ABCD1. These results expand the genetic spectrum of HSP patients in Serbia and the region with implications for molecular genetic diagnosis and future causative therapies. Wide HSP panel can be the first step in diagnosis, alongside with the copy number variation (CNV) analysis, while WES should be performed after.
{"title":"Whole exome sequencing in Serbian patients with hereditary spastic paraplegia.","authors":"Marija Brankovic, Vukan Ivanovic, Ivana Basta, Rin Khang, Eugene Lee, Zorica Stevic, Branislav Ralic, Radoje Tubic, GoHun Seo, Vladana Markovic, Ivo Bozovic, Marina Svetel, Ana Marjanovic, Nikola Veselinovic, Sarlota Mesaros, Milena Jankovic, Dusanka Savic-Pavicevic, Zita Jovin, Ivana Novakovic, Hane Lee, Stojan Peric","doi":"10.1007/s10048-024-00755-x","DOIUrl":"10.1007/s10048-024-00755-x","url":null,"abstract":"<p><p>Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases with a high genetic and clinical heterogeneity. Numerous HSP patients remain genetically undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel variants and genes is needed. Our previous study analyzed 74 adult Serbian HSP patients from 65 families using panel of the 13 most common HSP genes in combination with a copy number variation analysis. Conclusive genetic findings were established in 23 patients from 19 families (29%). In the present study, nine patients from nine families previously negative on the HSP gene panel were selected for the whole exome sequencing (WES). Further, 44 newly diagnosed adult HSP patients from 44 families were sent to WES directly, since many studies showed WES may be used as the first step in HSP diagnosis. WES analysis of cohort 1 revealed a likely genetic cause in five (56%) of nine HSP families, including variants in the ETHE1, ZFYVE26, RNF170, CAPN1, and WASHC5 genes. In cohort 2, possible causative variants were found in seven (16%) of 44 patients (later updated to 27% when other diagnosis were excluded), comprising six different genes: SPAST, SPG11, WASCH5, KIF1A, KIF5A, and ABCD1. These results expand the genetic spectrum of HSP patients in Serbia and the region with implications for molecular genetic diagnosis and future causative therapies. Wide HSP panel can be the first step in diagnosis, alongside with the copy number variation (CNV) analysis, while WES should be performed after.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140159662","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}
Multiple sclerosis (MS), an intricate neurological disorder, continues to challenge our understanding of the pivotal interplay between the immune system and the central nervous system (CNS). This condition arises from the immune system's misdirected attack on nerve fiber protection, known as myelin sheath, alongside nerve fibers themselves. This enigmatic condition, characterized by demyelination and varied clinical manifestations, prompts exploration into its multifaceted etiology and potential therapeutic avenues. Research has revealed a potential connection between Epstein Barr virus (EBV), specifically Epstein Barr Nuclear Antigen 1 (EBNA-1), and MS. The immune response to EBNA-1 antigen triggers the production of anti-EBNA-1 molecules, including IgG that identify a similar amino acid sequence to EBNA-1 in myelin, inadvertently targeting myelin sheath and contributing to MS progression. Currently, no treatment exists for EBNA-1-induced MS apart from symptom management. Addressing this, a novel potential therapeutic avenue utilizing small interference RNAs (siRNA) has been designed. By targeting the conserved EBNA-1 gene sequences in EBV types 1 and 2, five potential siRNAs were identified in our analysis. Thorough evaluations encompassing off-target binding, thermodynamics and secondary structure elucidation, efficacy prediction, siRNA-mRNA sequence binding affinity exploration, melting temperature, and docking of siRNAs with human argonaute protein 2 (AGO2) were conducted to elucidate the siRNAs efficiency. These designed siRNA molecules harnessed promising silencing activity in the EBNA-1 gene encoding the EBNA-1 antigen protein and thus have the potential to mitigate the severity of this dangerous virus.
{"title":"Hitting Epstein Barr virus where it hurts: computational methods exploration for siRNA therapy in alleviating Epstein Barr virus-induced multiple sclerosis.","authors":"Taiwo Ooreoluwa Ojo, Oluwabamise Emmanuel Elegbeleye, Olawale Quadri Bolaji, Temitope Isaac Adelusi, Elijah Kolawole Oladipo, Matthew Oluwaseun Olawuyi, Bukola Oluwafunmilayo Afolayan, Adegboye Oyewole Oyaronbi, Taiwo Temitope Ogunjobi, Moyosoluwa Precious Oyewole, Kolade Pelumi Folorunso, Abdeen Tunde Ogunlana","doi":"10.1007/s10048-024-00764-w","DOIUrl":"10.1007/s10048-024-00764-w","url":null,"abstract":"<p><p>Multiple sclerosis (MS), an intricate neurological disorder, continues to challenge our understanding of the pivotal interplay between the immune system and the central nervous system (CNS). This condition arises from the immune system's misdirected attack on nerve fiber protection, known as myelin sheath, alongside nerve fibers themselves. This enigmatic condition, characterized by demyelination and varied clinical manifestations, prompts exploration into its multifaceted etiology and potential therapeutic avenues. Research has revealed a potential connection between Epstein Barr virus (EBV), specifically Epstein Barr Nuclear Antigen 1 (EBNA-1), and MS. The immune response to EBNA-1 antigen triggers the production of anti-EBNA-1 molecules, including IgG that identify a similar amino acid sequence to EBNA-1 in myelin, inadvertently targeting myelin sheath and contributing to MS progression. Currently, no treatment exists for EBNA-1-induced MS apart from symptom management. Addressing this, a novel potential therapeutic avenue utilizing small interference RNAs (siRNA) has been designed. By targeting the conserved EBNA-1 gene sequences in EBV types 1 and 2, five potential siRNAs were identified in our analysis. Thorough evaluations encompassing off-target binding, thermodynamics and secondary structure elucidation, efficacy prediction, siRNA-mRNA sequence binding affinity exploration, melting temperature, and docking of siRNAs with human argonaute protein 2 (AGO2) were conducted to elucidate the siRNAs efficiency. These designed siRNA molecules harnessed promising silencing activity in the EBNA-1 gene encoding the EBNA-1 antigen protein and thus have the potential to mitigate the severity of this dangerous virus.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141162500","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}
Pub Date : 2024-07-01Epub Date: 2024-05-22DOI: 10.1007/s10048-024-00763-x
Lucas Cunha Barbosa, Gabriel Cardoso Machado, Manoela Heringer, Valéria Pereira Ferrer
Glioblastomas (GBM) are aggressive tumors known for their heterogeneity, rapid proliferation, treatment resistance, and extensive vasculature. Angiogenesis, the formation of new vessels, involves endothelial cell (EC) migration and proliferation. Various extracellular matrix (ECM) molecules regulate EC survival, migration, and proliferation. Culturing human brain EC (HBMEC) on GBM-derived ECM revealed a decrease in EC numbers compared to controls. Through in silico analysis, we explored ECM gene expression differences between GBM and brain normal glia cells and the impact of GBM microenvironment on EC ECM transcripts. ECM molecules such as collagen alpha chains (COL4A1, COL4A2, p < 0.0001); laminin alpha (LAMA4), beta (LAMB2), and gamma (LAMC1) chains (p < 0.0005); neurocan (NCAN), brevican (BCAN) and versican (VCAN) (p < 0.0005); hyaluronan synthase (HAS) 2 and metalloprotease (MMP) 2 (p < 0.005); MMP inhibitors (TIMP1-4, p < 0.0005), transforming growth factor beta-1 (TGFB1) and integrin alpha (ITGA3/5) (p < 0.05) and beta (ITGB1, p < 0.0005) chains showed increased expression in GBM. Additionally, GBM-influenced EC exhibited elevated expression of COL5A3, COL6A1, COL22A1 and COL27A1 (p < 0.01); LAMA1, LAMB1 (p < 0.001); fibulins (FBLN1/2, p < 0.01); MMP9, HAS1, ITGA3, TGFB1, and wingless-related integration site 9B (WNT9B) (p < 0.01) compared to normal EC. Some of these molecules: COL5A1/3, COL6A1, COL22/27A1, FBLN1/2, ITGA3/5, ITGB1 and LAMA1/B1 (p < 0.01); NCAN, HAS1, MMP2/9, TIMP1/2 and TGFB1 (p < 0.05) correlated with GBM patient survival. In conclusion, this study identified both established and novel ECM molecules regulating GBM angiogenesis, suggesting NCAN and COL27A1 are new potential prognostic biomarkers for GBM.
{"title":"Identification of established and novel extracellular matrix components in glioblastoma as targets for angiogenesis and prognosis.","authors":"Lucas Cunha Barbosa, Gabriel Cardoso Machado, Manoela Heringer, Valéria Pereira Ferrer","doi":"10.1007/s10048-024-00763-x","DOIUrl":"10.1007/s10048-024-00763-x","url":null,"abstract":"<p><p>Glioblastomas (GBM) are aggressive tumors known for their heterogeneity, rapid proliferation, treatment resistance, and extensive vasculature. Angiogenesis, the formation of new vessels, involves endothelial cell (EC) migration and proliferation. Various extracellular matrix (ECM) molecules regulate EC survival, migration, and proliferation. Culturing human brain EC (HBMEC) on GBM-derived ECM revealed a decrease in EC numbers compared to controls. Through in silico analysis, we explored ECM gene expression differences between GBM and brain normal glia cells and the impact of GBM microenvironment on EC ECM transcripts. ECM molecules such as collagen alpha chains (COL4A1, COL4A2, p < 0.0001); laminin alpha (LAMA4), beta (LAMB2), and gamma (LAMC1) chains (p < 0.0005); neurocan (NCAN), brevican (BCAN) and versican (VCAN) (p < 0.0005); hyaluronan synthase (HAS) 2 and metalloprotease (MMP) 2 (p < 0.005); MMP inhibitors (TIMP1-4, p < 0.0005), transforming growth factor beta-1 (TGFB1) and integrin alpha (ITGA3/5) (p < 0.05) and beta (ITGB1, p < 0.0005) chains showed increased expression in GBM. Additionally, GBM-influenced EC exhibited elevated expression of COL5A3, COL6A1, COL22A1 and COL27A1 (p < 0.01); LAMA1, LAMB1 (p < 0.001); fibulins (FBLN1/2, p < 0.01); MMP9, HAS1, ITGA3, TGFB1, and wingless-related integration site 9B (WNT9B) (p < 0.01) compared to normal EC. Some of these molecules: COL5A1/3, COL6A1, COL22/27A1, FBLN1/2, ITGA3/5, ITGB1 and LAMA1/B1 (p < 0.01); NCAN, HAS1, MMP2/9, TIMP1/2 and TGFB1 (p < 0.05) correlated with GBM patient survival. In conclusion, this study identified both established and novel ECM molecules regulating GBM angiogenesis, suggesting NCAN and COL27A1 are new potential prognostic biomarkers for GBM.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141077242","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}
Pub Date : 2024-07-01Epub Date: 2024-05-17DOI: 10.1007/s10048-024-00762-y
Wiktoria Radziwonik-Fraczyk, Ewelina Elert-Dobkowska, Marek Karpinski, Jacek Pilch, Karolina Ziora-Jakutowicz, Jolanta Kubalska, Dominika Szczesniak, Iwona Stepniak, Jacek Zaremba, Anna Sulek
Neuromuscular disorders (NMDs) include a wide range of diseases affecting the peripheral nervous system. The genetic diagnoses are increasingly obtained with using the next generation sequencing (NGS). We applied the custom-design targeted NGS panel including 89 genes, together with genotyping and multiplex ligation-dependent probe amplification (MLPA) to identify a genetic spectrum of NMDs in 52 Polish patients. As a result, the genetic diagnosis was determined by NGS panel in 29 patients so its diagnostic utility is estimated at 55.8%. The most pathogenic variants were found in CLCN1, followed by CAPN3, SCN4A, and SGCA genes. Genotyping of myotonic dystrophy type 1 and 2 (DM1 and DM2) as a secondary approach has been performed. The co-occurrence of CAPN3 and CNBP mutations in one patient as well as DYSF and CNBP mutations in another suggests possibly more complex inheritance as well as expression of a phenotype. In 7 individuals with single nucleotide variant found in NGS testing, the MLPA of the CAPN3 gene was performed detecting the deletion encompassing exons 2-8 in the CAPN3 gene in one patient, confirming recessive limb-girdle muscular dystrophy type 1 (LGMDR1). Thirty patients obtained a genetic diagnosis (57.7%) after using NGS testing, genotyping and MLPA analysis. The study allowed for the identification of 27 known and 4 novel pathogenic/likely pathogenic variants and variants of uncertain significance (VUS) associated with NMDs.In conclusion, the diagnostic approach with diverse molecular techniques enables to broaden the mutational spectrum and maximizes the diagnostic yield. Furthermore, the co-occurrence of DM2 and LGMD has been detected in 2 individuals.
{"title":"Next generation sequencing panel as an effective approach to genetic testing in patients with a highly variable phenotype of neuromuscular disorders.","authors":"Wiktoria Radziwonik-Fraczyk, Ewelina Elert-Dobkowska, Marek Karpinski, Jacek Pilch, Karolina Ziora-Jakutowicz, Jolanta Kubalska, Dominika Szczesniak, Iwona Stepniak, Jacek Zaremba, Anna Sulek","doi":"10.1007/s10048-024-00762-y","DOIUrl":"10.1007/s10048-024-00762-y","url":null,"abstract":"<p><p>Neuromuscular disorders (NMDs) include a wide range of diseases affecting the peripheral nervous system. The genetic diagnoses are increasingly obtained with using the next generation sequencing (NGS). We applied the custom-design targeted NGS panel including 89 genes, together with genotyping and multiplex ligation-dependent probe amplification (MLPA) to identify a genetic spectrum of NMDs in 52 Polish patients. As a result, the genetic diagnosis was determined by NGS panel in 29 patients so its diagnostic utility is estimated at 55.8%. The most pathogenic variants were found in CLCN1, followed by CAPN3, SCN4A, and SGCA genes. Genotyping of myotonic dystrophy type 1 and 2 (DM1 and DM2) as a secondary approach has been performed. The co-occurrence of CAPN3 and CNBP mutations in one patient as well as DYSF and CNBP mutations in another suggests possibly more complex inheritance as well as expression of a phenotype. In 7 individuals with single nucleotide variant found in NGS testing, the MLPA of the CAPN3 gene was performed detecting the deletion encompassing exons 2-8 in the CAPN3 gene in one patient, confirming recessive limb-girdle muscular dystrophy type 1 (LGMDR1). Thirty patients obtained a genetic diagnosis (57.7%) after using NGS testing, genotyping and MLPA analysis. The study allowed for the identification of 27 known and 4 novel pathogenic/likely pathogenic variants and variants of uncertain significance (VUS) associated with NMDs.In conclusion, the diagnostic approach with diverse molecular techniques enables to broaden the mutational spectrum and maximizes the diagnostic yield. Furthermore, the co-occurrence of DM2 and LGMD has been detected in 2 individuals.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140961153","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}
Pub Date : 2024-07-01Epub Date: 2024-05-25DOI: 10.1007/s10048-024-00759-7
Saima, Amjad Khan, Sajid Ali, Jiuhong Jiang, Zhichao Miao, Atif Kamil, Shahid Niaz Khan, Stefan T Arold
Primary microcephaly is a rare neurogenic and genetically heterogeneous disorder characterized by significant brain size reduction that results in numerous neurodevelopmental disorders (NDD) problems, including mild to severe intellectual disability (ID), global developmental delay (GDD), seizures and other congenital malformations. This disorder can arise from a mutation in genes involved in various biological pathways, including those within the brain. We characterized a recessive neurological disorder observed in nine young adults from five independent consanguineous Pakistani families. The disorder is characterized by microcephaly, ID, developmental delay (DD), early-onset epilepsy, recurrent infection, hearing loss, growth retardation, skeletal and limb defects. Through exome sequencing, we identified novel homozygous variants in five genes that were previously associated with brain diseases, namely CENPJ (NM_018451.5: c.1856A > G; p.Lys619Arg), STIL (NM_001048166.1: c.1235C > A; p.(Pro412Gln), CDK5RAP2 (NM_018249.6 c.3935 T > G; p.Leu1312Trp), RBBP8 (NM_203291.2 c.1843C > T; p.Gln615*) and CEP135 (NM_025009.5 c.1469A > G; p.Glu490Gly). These variants were validated by Sanger sequencing across all family members, and in silico structural analysis. Protein 3D homology modeling of wild-type and mutated proteins revealed substantial changes in the structure, suggesting a potential impact on function. Importantly, all identified genes play crucial roles in maintaining genomic integrity during cell division, with CENPJ, STIL, CDK5RAP2, and CEP135 being involved in centrosomal function. Collectively, our findings underscore the link between erroneous cell division, particularly centrosomal function, primary microcephaly and ID.
{"title":"Clinical genomics expands the link between erroneous cell division, primary microcephaly and intellectual disability.","authors":"Saima, Amjad Khan, Sajid Ali, Jiuhong Jiang, Zhichao Miao, Atif Kamil, Shahid Niaz Khan, Stefan T Arold","doi":"10.1007/s10048-024-00759-7","DOIUrl":"10.1007/s10048-024-00759-7","url":null,"abstract":"<p><p>Primary microcephaly is a rare neurogenic and genetically heterogeneous disorder characterized by significant brain size reduction that results in numerous neurodevelopmental disorders (NDD) problems, including mild to severe intellectual disability (ID), global developmental delay (GDD), seizures and other congenital malformations. This disorder can arise from a mutation in genes involved in various biological pathways, including those within the brain. We characterized a recessive neurological disorder observed in nine young adults from five independent consanguineous Pakistani families. The disorder is characterized by microcephaly, ID, developmental delay (DD), early-onset epilepsy, recurrent infection, hearing loss, growth retardation, skeletal and limb defects. Through exome sequencing, we identified novel homozygous variants in five genes that were previously associated with brain diseases, namely CENPJ (NM_018451.5: c.1856A > G; p.Lys619Arg), STIL (NM_001048166.1: c.1235C > A; p.(Pro412Gln), CDK5RAP2 (NM_018249.6 c.3935 T > G; p.Leu1312Trp), RBBP8 (NM_203291.2 c.1843C > T; p.Gln615*) and CEP135 (NM_025009.5 c.1469A > G; p.Glu490Gly). These variants were validated by Sanger sequencing across all family members, and in silico structural analysis. Protein 3D homology modeling of wild-type and mutated proteins revealed substantial changes in the structure, suggesting a potential impact on function. Importantly, all identified genes play crucial roles in maintaining genomic integrity during cell division, with CENPJ, STIL, CDK5RAP2, and CEP135 being involved in centrosomal function. Collectively, our findings underscore the link between erroneous cell division, particularly centrosomal function, primary microcephaly and ID.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141097003","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}