Neurogenetics最新文献_第3页

Phenotype-genotype spectrum of a cohort of congenital muscular dystrophies: a single-centre experience from India. 一组先天性肌营养不良症的表型-基因型谱：来自印度的单中心经验。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-10-01 Epub Date: 2024-08-05 DOI: 10.1007/s10048-024-00776-6

Tanushree Chawla, Saraswati Nashi, Dipti Baskar, Kiran Polavarapu, Seena Vengalil, Mainak Bardhan, Veeramani Preethish-Kumar, Ramya Sukrutha, Gopikrishnan Unnikrishnan, Akshata Huddar, Hansashree Padmanabha, Ram Murthy Anjanappa, Nandeesh Bevinahalli, Vidya Nittur, Manoj Rajanna, Gautham Arunachal Udupi, Atchayaram Nalini

{"title":"Phenotype-genotype spectrum of a cohort of congenital muscular dystrophies: a single-centre experience from India.","authors":"Tanushree Chawla, Saraswati Nashi, Dipti Baskar, Kiran Polavarapu, Seena Vengalil, Mainak Bardhan, Veeramani Preethish-Kumar, Ramya Sukrutha, Gopikrishnan Unnikrishnan, Akshata Huddar, Hansashree Padmanabha, Ram Murthy Anjanappa, Nandeesh Bevinahalli, Vidya Nittur, Manoj Rajanna, Gautham Arunachal Udupi, Atchayaram Nalini","doi":"10.1007/s10048-024-00776-6","DOIUrl":"10.1007/s10048-024-00776-6","url":null,"abstract":"Congenital Muscular Dystrophies (CMD) are phenotypically and genotypically heterogenous disorders with a prevalence of 0.68 to 2.5/100,000, contributing to significant morbidity and mortality. We aimed to study the phenotype-genotype spectrum of genetically confirmed cases of CMD. This was retrospective & descriptive study done at a quaternary care referral centre in south India. Genetically confirmed cases of CMDs seen between 2010 to 2020 were recruited. Detailed clinical history, including pedigree, MRI brain/muscle, next generation sequencing results of 61 CMD cases were collected. Collagen VI-related dystrophy (COL6-RD) (36%) was the most common subtype with variants frequently seen in COL6A1 gene. Other CMDs identified were LAMA2-RD (26%), alpha-dystroglycan-RD (19%), LMNA-RD (8%), CHKB-RD (7%) and SEPN1-RD (3%). Similar to previous cohorts, overall, missense variants were common in COL-6 RD. Variants in triple helical domain (THD) of COL6-RD were seen in 11/22 patients, 5 of whom were ambulatory contrary to previous literature citing severe disease with these variants. However, our follow-up period was shorter. In the LAMA2-RD, 2/16 patients were ambulatory & all 16 carried truncating variants. Among dystroglycanopathies, FKRP-RD was the commonest. Milder phenotype of FKRP- RD was observed with variant c.1343C > T, which was also a recurrent variant in our cohort. p.Arg249Trp variant in LMNA-CMD associated with early loss of ambulation was also identified in 1/5 of our patients who expired at age 2.8 years. The current retrospective series provides detailed clinical features and mutation patterns of genetically confirmed cases of CMD from a single center in India.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"435-469"},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894930","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

Novel splicing variant and gonadal mosaicism in DYRK1A gene identified by whole-genome sequencing in multiplex autism spectrum disorder families. 通过全基因组测序在多重自闭症谱系障碍家族中发现 DYRK1A 基因的新剪接变异和性腺嵌合。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-10-01 Epub Date: 2024-07-08 DOI: 10.1007/s10048-024-00768-6

Mehdi Agha Gholizadeh, Farkhondeh Behjati, Saghar Ghasemi Firouzabadi, Erfan Heidari, Ehsan Razmara, Navid Almadani, Ali Sharifi Zarchi, Masoud Garshasbi

{"title":"Novel splicing variant and gonadal mosaicism in DYRK1A gene identified by whole-genome sequencing in multiplex autism spectrum disorder families.","authors":"Mehdi Agha Gholizadeh, Farkhondeh Behjati, Saghar Ghasemi Firouzabadi, Erfan Heidari, Ehsan Razmara, Navid Almadani, Ali Sharifi Zarchi, Masoud Garshasbi","doi":"10.1007/s10048-024-00768-6","DOIUrl":"10.1007/s10048-024-00768-6","url":null,"abstract":"Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with considerable genetic heterogeneity. The disorder is clinically diagnosed based on DSM-5 criteria, featuring deficits in social communication and interaction, along with restricted and repetitive behaviours. Here, we performed whole-genome sequencing (WGS) on four individuals with ASD from two multiplex families (MPX), where more than one individual is affected, to identify potential single nucleotide variants (SNVs) and structural variants (SVs) in coding and non-coding regions. A rigorous bioinformatics pipeline was employed for variant detection, followed by segregation analysis. Our investigation revealed an unreported splicing variant in the DYRK1A gene (c.-77 + 2T > C; IVS1 + 2T > C; NM_001396.5), in heterozygote form in two affected children in one of the families (family B), which was absent in the healthy parents and siblings. This finding suggests the presence of gonadal mosaicism in one of the parents, representing the first documented instance of such inheritance for a variant in the DYRK1A gene associated with ASD. Furthermore, we identified a 50 bp deletion in intron 9 of the DLG2 gene in two affected patients from the same family, confirmed by PCR and Sanger sequencing. In Family A, we identified potential candidate variants associated with ASD shared by the two patients. These findings enhance our understanding of the genetic landscape of ASD, particularly in MPX families, and highlight the utility of WGS in uncovering novel genetic contributions to neurodevelopmental disorders.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"377-391"},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141556068","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":" ","pages":"367-375"},"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 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":" ","pages":"417-424"},"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

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":"44 1","pages":""},"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":" ","pages":"201-213"},"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":" ","pages":"193-200"},"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":" ","pages":"165-177"},"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":" ","pages":"263-275"},"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