Neurogenetics最新文献_第2页

The lethal homozygous variant in the ATP1A2 gene is associated with FARIMPD syndrome phenotypes in newborns. ATP1A2 基因的致命同源变异与新生儿的 FARIMPD 综合征表型有关。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-10-01 Epub Date: 2024-07-24 DOI: 10.1007/s10048-024-00775-7

Behzad Haj Mohammad Hassani, Kianoosh Malekzadeh

{"title":"The lethal homozygous variant in the ATP1A2 gene is associated with FARIMPD syndrome phenotypes in newborns.","authors":"Behzad Haj Mohammad Hassani, Kianoosh Malekzadeh","doi":"10.1007/s10048-024-00775-7","DOIUrl":"10.1007/s10048-024-00775-7","url":null,"abstract":"FARIMPD (Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies) syndrome is a severe condition caused by ATP1A2 gene variants. The syndrome's novelty and rarity have limited its clinical and molecular knowledge. This research tries to provide new insight by investigating the cause of the early deaths due to FARIMPD syndrome in a particular family and reviewing previous studies. DNA and RNA were extracted from the blood samples of newborns and their parents, followed by whole exome sequencing and segregation analysis. A pathogenic homozygous nonsense variant (c.1234C > T: p.Arg412*) in the ATP1A2 gene was found in newborns. This variant is reported as homozygous for the first time. The migraine symptoms were the result of the heterozygous state of this particular variant, which supported the dominant inheritance pattern of this disease. Real-time PCR was used to analyze ATP1A2 gene expression in the newborns compared to parents and control subjects. The expression analysis also showed significant mRNA degradation in the newborns compared to heterozygous and healthy individuals, due to Nonsense-mediated mRNA Decay phenomena. Our study describes an ATP1A2 nonsense variant (c.1234C > T) that appears compatible with infant survival in the heterozygous and compound heterozygous states but is lethal in the homozygous state.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141753491","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}

引用次数: 0

TREK-1 channel as a therapeutic target for dexmedetomidine-mediated neuroprotection in cerebral ischemia. TREK-1通道作为右美托咪定介导的脑缺血神经保护治疗靶点

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-10-01 Epub Date: 2024-07-08 DOI: 10.1007/s10048-024-00772-w

Yang Xu, XiaoDan Teng, Ming Wei, Yang Liu

{"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":"10.1007/s10048-024-00772-w","url":null,"abstract":"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.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","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}

引用次数: 0

The role of gut-derived short-chain fatty acids in Parkinson's disease 肠道短链脂肪酸在帕金森病中的作用

IF 2.2 4区医学

Neurogenetics Pub Date : 2024-09-13 DOI: 10.1007/s10048-024-00779-3

Mohamed J. Saadh, Anfal Nabeel Mustafa, Mohammed Ahmed Mustafa, Renuka Jyothi. S, Hasan Khalid Dabis, G. V. Siva Prasad, Imad Jassim Mohammad, Ahmed Adnan, Ameer Hassan Idan

引用次数: 0

A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability of ATP8A2-related disorders caused by missense changes ATP8A2的ATPase结构域中的一种新型错义变异，以及由错义变异引起的ATP8A2相关疾病的表型变异综述

IF 2.2 4区医学

Neurogenetics Pub Date : 2024-07-27 DOI: 10.1007/s10048-024-00773-9

Kyle P. Flannery, Sylvia Safwat, Eli Matsell, Namarata Battula, Ahlam A. A. Hamed, Inaam N. Mohamed, Maha A. Elseed, Mahmoud Koko, Rayan Abubaker, Fatima Abozar, Liena E. O. Elsayed, Vikram Bhise, Robert S. Molday, Mustafa A. Salih, Ashraf Yahia, M. Chiara Manzini

{"title":"A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability of ATP8A2-related disorders caused by missense changes","authors":"Kyle P. Flannery, Sylvia Safwat, Eli Matsell, Namarata Battula, Ahlam A. A. Hamed, Inaam N. Mohamed, Maha A. Elseed, Mahmoud Koko, Rayan Abubaker, Fatima Abozar, Liena E. O. Elsayed, Vikram Bhise, Robert S. Molday, Mustafa A. Salih, Ashraf Yahia, M. Chiara Manzini","doi":"10.1007/s10048-024-00773-9","DOIUrl":"https://doi.org/10.1007/s10048-024-00773-9","url":null,"abstract":"ATPase, class 1, type 8 A, member 2 (ATP8A2) is a P4-ATPase with a critical role in phospholipid translocation across the plasma membrane. Pathogenic variants in ATP8A2 are known to cause cerebellar ataxia, impaired intellectual development, and disequilibrium syndrome 4 (CAMRQ4) which is often associated with encephalopathy, global developmental delay, and severe motor deficits. Here, we present a family with two siblings born from a consanguineous, first-cousin union from Sudan presenting with global developmental delay, intellectual disability, spasticity, ataxia, nystagmus, and thin corpus callosum. Whole exome sequencing revealed a homozygous missense variant in the nucleotide binding domain of ATP8A2 (p.Leu538Pro) that results in near complete loss of protein expression. This is in line with other missense variants in the same domain leading to protein misfolding and loss of ATPase function. In addition, by performing diffusion-weighted imaging, we identified bilateral hyperintensities in the posterior limbs of the internal capsule suggesting possible microstructural changes in axon tracts that had not been appreciated before and could contribute to the sensorimotor deficits in these individuals.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141781124","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}

引用次数: 0

Investigation of genotype-phenotype and familial features of Turkish dystrophinopathy patients. 土耳其肌营养不良症患者的基因型-表型和家族特征调查。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-07-01 Epub Date: 2024-06-08 DOI: 10.1007/s10048-024-00765-9

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

{"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":"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.","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}

引用次数: 0

Frequency of C9orf72, GRN, and MAPT pathogenic variants in patients recruited at the Belgrade Memory Center. 贝尔格莱德记忆中心招募的患者中 C9orf72、GRN 和 MAPT 致病变体的频率。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-07-01 Epub Date: 2024-06-07 DOI: 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

{"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":"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.","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}

引用次数: 0

Whole exome sequencing in Serbian patients with hereditary spastic paraplegia. 塞尔维亚遗传性痉挛性截瘫患者的全外显子组测序。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-07-01 Epub Date: 2024-03-19 DOI: 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

{"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":"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.","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}

引用次数: 0

Hitting Epstein Barr virus where it hurts: computational methods exploration for siRNA therapy in alleviating Epstein Barr virus-induced multiple sclerosis. 直击爱泼斯坦-巴氏病毒要害：探索 siRNA 治疗缓解爱泼斯坦-巴氏病毒诱发的多发性硬化症的计算方法。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-07-01 Epub Date: 2024-05-29 DOI: 10.1007/s10048-024-00764-w

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

{"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":"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.","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}

引用次数: 0

Identification of established and novel extracellular matrix components in glioblastoma as targets for angiogenesis and prognosis. 鉴定胶质母细胞瘤中作为血管生成和预后靶点的既有和新型细胞外基质成分。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-07-01 Epub Date: 2024-05-22 DOI: 10.1007/s10048-024-00763-x

Lucas Cunha Barbosa, Gabriel Cardoso Machado, Manoela Heringer, Valéria Pereira Ferrer

{"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":"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.","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}

引用次数: 0

Next generation sequencing panel as an effective approach to genetic testing in patients with a highly variable phenotype of neuromuscular disorders. 下一代测序面板是对表型千变万化的神经肌肉疾病患者进行基因检测的有效方法。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-07-01 Epub Date: 2024-05-17 DOI: 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

{"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":"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.","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}

引用次数: 0