Human Genetics最新文献_第3页

Congenital enteropathy caused by ezrin deficiency. 由ezrin缺乏引起的先天性肠病。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-05-01 Epub Date: 2025-03-26 DOI: 10.1007/s00439-025-02738-w

Georg F Vogel, Katharina M C Klee, Arzu Meltem Demir, Dorota Garczarczyk-Asim, Michael W Hess, Lukas A Huber, Thomas Müller, Andreas R Janecke

{"title":"Congenital enteropathy caused by ezrin deficiency.","authors":"Georg F Vogel, Katharina M C Klee, Arzu Meltem Demir, Dorota Garczarczyk-Asim, Michael W Hess, Lukas A Huber, Thomas Müller, Andreas R Janecke","doi":"10.1007/s00439-025-02738-w","DOIUrl":"10.1007/s00439-025-02738-w","url":null,"abstract":"Ezrin, encoded by EZR, is a central module of epithelial polarity and links membrane proteins to the actin cytoskeleton directly or indirectly through scaffold proteins in the epithelium. Ezrin knockout mice fail to thrive and do not survive past weaning. We identified a homozygous EZR loss-of-function (LoF) variant, c.356dup, by exome sequencing in an infant with intractable diarrhea and failure to thrive, who died from septicemia at 5 months of age. The variant localized within a homozygous region of 13.2 Mb in the proband, is consistent with inheritance identical-by-descent from the consanguineous parents, and segregated with disease in the proband's family. EZR transcript analyses in a heterozygous carrier showed that the variant triggers nonsense-mediated mRNA decay. Homozygous EZR LoF variants have not been reported in public databases. In this study, we generated a Caco-2 EZR knockout cell line to investigate the role of ezrin in human intestinal epithelia. Our analyses used electron and immunofluorescence microscopy to assess structural changes in the knockout cells. We observed significant disorganization of the terminal web region, microvillus rarefaction and abnormal branching. Furthermore, the absence of ezrin resulted in the mislocalization of the ezrin-interacting scaffold protein Na+/H + exchanger regulatory factor-1. In conclusion, this represents the first documentation of complete ezrin deficiency in humans, highlighting the essential and non-redundant functions of the protein in maintaining intestinal physiology.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"505-514"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A latent outcome variable approach for Mendelian randomization using the stochastic expectation maximization algorithm. 使用随机期望最大化算法的孟德尔随机化的潜在结果变量方法。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-05-01 Epub Date: 2025-04-11 DOI: 10.1007/s00439-025-02739-9

Lamessa Dube Amente, Natalie T Mills, Thuc Duy Le, Elina Hyppönen, S Hong Lee

{"title":"A latent outcome variable approach for Mendelian randomization using the stochastic expectation maximization algorithm.","authors":"Lamessa Dube Amente, Natalie T Mills, Thuc Duy Le, Elina Hyppönen, S Hong Lee","doi":"10.1007/s00439-025-02739-9","DOIUrl":"https://doi.org/10.1007/s00439-025-02739-9","url":null,"abstract":"Mendelian randomization (MR) is a widely used tool to uncover causal relationships between exposures and outcomes. However, existing MR methods can suffer from inflated type I error rates and biased causal effects in the presence of invalid instruments. Our proposed method enhances MR analysis by augmenting latent phenotypes of the outcome, explicitly disentangling horizontal and vertical pleiotropy effects. This allows for explicit assessment of the exclusion restriction assumption and iteratively refines causal estimates through the expectation-maximization algorithm. This approach offers a unique and potentially more precise framework compared to existing MR methods. We rigorously evaluate our method against established MR approaches across diverse simulation scenarios, including balanced and directional pleiotropy, as well as violations of the Instrument Strength Independent of Direct Effect (InSIDE) assumption. Our findings consistently demonstrate superior performance of our method in terms of controlling type I error rates, bias, and robustness to genetic confounding, regardless of whether individual-level or summary data is used. Additionally, our method facilitates testing for directional horizontal pleiotropy and outperforms MR-Egger in this regard, while also effectively testing for violations of the InSIDE assumption. We apply our method to real data, demonstrating its effectiveness compared to traditional MR methods. This analysis reveals the causal effects of body mass index (BMI) on metabolic syndrome (MetS) and a composite MetS score calculated by the weighted sum of its component factors. While the causal relationship is consistent across most methods, our proposed method shows fewer violations of the exclusion restriction assumption, especially for MetS scores where horizontal pleiotropy persists and other methods suffer from inflation.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"144 5","pages":"559-574"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advancing chronic myeloid leukemia research with next-generation sequencing: potential benefits, limitations, and future clinical integration. 利用新一代测序技术推进慢性髓性白血病研究：潜在益处、局限性和未来临床整合。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-05-01 Epub Date: 2025-04-21 DOI: 10.1007/s00439-025-02745-x

Henry Sutanto, Laras Pratiwi, Pradana Zaky Romadhon, Siprianus Ugroseno Yudho Bintoro

{"title":"Advancing chronic myeloid leukemia research with next-generation sequencing: potential benefits, limitations, and future clinical integration.","authors":"Henry Sutanto, Laras Pratiwi, Pradana Zaky Romadhon, Siprianus Ugroseno Yudho Bintoro","doi":"10.1007/s00439-025-02745-x","DOIUrl":"https://doi.org/10.1007/s00439-025-02745-x","url":null,"abstract":"Next-generation sequencing (NGS) has emerged as a powerful tool for advancing research in chronic myeloid leukemia (CML) by providing a deeper understanding of its genetic complexity. Beyond detecting the hallmark BCR::ABL1 fusion gene, NGS has enabled the identification of additional mutations associated with disease progression, therapy resistance, and clonal evolution. NGS also facilitates the detection of rare BCR::ABL1 fusion variants and cryptic rearrangements, offering a more refined genetic characterization of the disease. Additionally, it enhances the study of minimal residual disease (MRD) and evolving resistance patterns, which are crucial for developing targeted therapeutic strategies. However, challenges such as data interpretation, standardization, and cost constraints continue to limit the widespread application of NGS in routine research and clinical settings. This review explores the contributions of NGS to CML research, highlighting its role in uncovering novel genetic alterations, tracking clonal evolution, and identifying potential therapeutic targets. As sequencing technologies evolve, NGS is expected to further shape the future of CML research, providing critical insights that may ultimately refine disease management strategies.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"144 5","pages":"481-503"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Decade-long application of preimplantation genetic testing for DMD/BMD: analysis of five clinical strategies and embryo recombination patterns. DMD/BMD植入前基因检测的十年应用：五种临床策略和胚胎重组模式分析。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-04-01 Epub Date: 2025-02-19 DOI: 10.1007/s00439-025-02728-y

Weili Wang, Jing Dai, Xiao Hu, Wenbin He, Yifan Gu, Zhenxing Wan, Yi Zhang, Keli Luo, Wen Li, Qianjun Zhang, Fei Gong, Guangxiu Lu, Liang Hu, Yue-Qiu Tan, Ge Lin, Juan Du

{"title":"Decade-long application of preimplantation genetic testing for DMD/BMD: analysis of five clinical strategies and embryo recombination patterns.","authors":"Weili Wang, Jing Dai, Xiao Hu, Wenbin He, Yifan Gu, Zhenxing Wan, Yi Zhang, Keli Luo, Wen Li, Qianjun Zhang, Fei Gong, Guangxiu Lu, Liang Hu, Yue-Qiu Tan, Ge Lin, Juan Du","doi":"10.1007/s00439-025-02728-y","DOIUrl":"10.1007/s00439-025-02728-y","url":null,"abstract":"This study aimed to find the most effective PGT-M strategy for Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD), and to reduce misdiagnosis caused by embryo recombination in DMD. A retrospective study was performed by analyzing 158 PGT-M cycles for DMD/BMD in Reproductive and Genetic Hospital of CITIC-Xiangya between 2009 and 2023. Patients' backgrounds were collected. The effectiveness and safety for five different PGT-M strategies (1-5), including mutation testing from cleavage or trophoblast ectoderm (TE) cells and additional linkage analysis post-TE cell amplification, were analyzed. The embryonic recombination events were assessed for these cycles. Mutation analysis showed that 62.4% of the 125 families had DMD deletions, 16.0% had duplications, and 21.6% had single nucleotide variants (SNVs). Among 125 families, 104 (83.2%) had previously affected fetus or offspring. The highest diagnosis rate (99.56%) was achieved with Strategy 5, which combined mutation testing with SNP-based linkage analysis in TE cells. This strategy 5 also demonstrated an advantage in cases with recombination near the mutation. An intragenic recombination rate of 5.5% was observed in embryos, predominantly in the hotspots (exons 45-55 and exons 3-9) of DMD deletion/duplication mutations. Prenatal diagnosis for 52 families and successful outcomes in all 85 healthy deliveries (live birth rate, 65.89%, 85/129) validated the accuracy and effectiveness of PGT-M. This study provides a highly effective PGT-M strategy (Strategy 5) for DMD/BMD by comparing five different strategies, with the diagnostic yield reaching 99.56%. The results underscore the significance of monitoring intragenic recombination in DMD, which is a frequent occurrence in DMD/BMD.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"405-416"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unilateral, bilateral symmetric or asymmetric isolated hearing loss in patients with heterozygous KITLG variants. 杂合子KITLG变异患者单侧、双侧对称或不对称孤立性听力损失。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-04-01 Epub Date: 2025-02-07 DOI: 10.1007/s00439-025-02730-4

Margaux Serey-Gaut, Ralyath Balogoun, Laurence Jonard, Geneviève Lina-Granade, Renaud Touraine, Marjolaine Willems, Nicola Hepp, Nanna Dahl Rendtorff, Mette Bertelsen, Natalie Loundon, Vincent Couloigner, Isabelle Lemiere, Judite de Oliveira, Serge Romana, Camille Porteret, Pierre Blanc, Luke Mansard, Sandrine Marlin, Anne-Françoise Roux, Véronique Pingault

{"title":"Unilateral, bilateral symmetric or asymmetric isolated hearing loss in patients with heterozygous KITLG variants.","authors":"Margaux Serey-Gaut, Ralyath Balogoun, Laurence Jonard, Geneviève Lina-Granade, Renaud Touraine, Marjolaine Willems, Nicola Hepp, Nanna Dahl Rendtorff, Mette Bertelsen, Natalie Loundon, Vincent Couloigner, Isabelle Lemiere, Judite de Oliveira, Serge Romana, Camille Porteret, Pierre Blanc, Luke Mansard, Sandrine Marlin, Anne-Françoise Roux, Véronique Pingault","doi":"10.1007/s00439-025-02730-4","DOIUrl":"10.1007/s00439-025-02730-4","url":null,"abstract":"KITLG pathogenic variants have been associated to three distinct clinical presentations with different combinations of hearing loss and/or pigmentation abnormalities. However, its involvement in isolated hearing loss has not been confirmed since its initial description in two families. Besides, KITLG is so far the only gene prevailingly involved in unilateral isolated hearing loss. We therefore conducted a retrospective study of patients with KITLG alterations in the French national Reference Network for Genetic Hearing Loss and one case was added through the Genematcher exchange platform. We describe a series of monoallelic KITLG deletions and variations in a cohort of 14 symptomatic patients from eight unrelated families. All patients presented with unilateral, bilateral symmetric or asymmetric sensorineural hearing loss. When not profound, hearing loss was predominant on low frequencies. Most KITLG alterations are likely to result in loss-of-function and aggregate in the extracellular region, disrupting the KIT-binding domain or its structure. Penetrance is not complete, and unspecific pigmentation alterations were observed in only three patients. The present study confirms KITLG involvement in isolated unilateral, bilateral symmetric or asymmetric hearing loss. This confirmation indicates that genetic testing can be relevant in early-onset, non-sudden, isolated unilateral hearing loss.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"433-441"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mendelian randomization analysis and molecular mechanism study of childhood asthma and obstructive sleep apnea. 儿童哮喘与阻塞性睡眠呼吸暂停的孟德尔随机化分析及分子机制研究。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-04-01 Epub Date: 2025-03-03 DOI: 10.1007/s00439-025-02734-0

Xinyu Wang, Lin Zhang, Hao Chen, Ting Tian, Lulu Wu, Yuping Huang, Qian Cao, Lili Zhuang, Guoping Zhou

{"title":"Mendelian randomization analysis and molecular mechanism study of childhood asthma and obstructive sleep apnea.","authors":"Xinyu Wang, Lin Zhang, Hao Chen, Ting Tian, Lulu Wu, Yuping Huang, Qian Cao, Lili Zhuang, Guoping Zhou","doi":"10.1007/s00439-025-02734-0","DOIUrl":"10.1007/s00439-025-02734-0","url":null,"abstract":"Childhood asthma is a common chronic respiratory disorder influenced by various factors, and obstructive sleep apnea (OSA) has emerged as a significant comorbidity. This study sought to investigate the underlying molecular mechanisms of the comorbidity between childhood asthma and OSA through Mendelian randomization (MR) analysis. Gene expression and genotype data were analyzed from public databases, and single nucleotide polymorphisms (SNPs) related to both diseases were identified. Our research findings unveiled 242 gene pairs associated with childhood asthma and 350 gene pairs related to OSA. Among them, the three hub genes, namely LRP3, BAK1, and CLIC4, exhibited significant expression alterations in both diseases. These hub genes participate in multiple signal transduction pathways and exhibit a remarkable correlation with the infiltration of immune cells, suggesting that they exert a vital role in modulating the immune microenvironment. Further analyses, encompassing gene set enrichment and transcriptional regulation, emphasized the complex interplay between these genes and non-coding RNAs as well as transcription factors. Our study results stressed the bidirectional relationship between childhood asthma and OSA and accentuated the significance of early identification and targeted intervention. This study identified potential therapeutic targets and laid a foundation for formulating treatment strategies aimed at improving the conditions of children with these interrelated diseases.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"443-461"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Human organoids for rapid validation of gene variants linked to cochlear malformations. 用于快速验证与耳蜗畸形相关的基因变异的人类类器官。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-04-01 Epub Date: 2025-01-09 DOI: 10.1007/s00439-024-02723-9

Mohammad Faraz Zafeer, Memoona Ramzan, Duygu Duman, Ahmet Mutlu, Serhat Seyhan, M Tayyar Kalcioglu, Suat Fitoz, Brooke A DeRosa, Shengru Guo, Derek M Dykxhoorn, Mustafa Tekin

{"title":"Human organoids for rapid validation of gene variants linked to cochlear malformations.","authors":"Mohammad Faraz Zafeer, Memoona Ramzan, Duygu Duman, Ahmet Mutlu, Serhat Seyhan, M Tayyar Kalcioglu, Suat Fitoz, Brooke A DeRosa, Shengru Guo, Derek M Dykxhoorn, Mustafa Tekin","doi":"10.1007/s00439-024-02723-9","DOIUrl":"10.1007/s00439-024-02723-9","url":null,"abstract":"Developmental anomalies of the hearing organ, the cochlea, are diagnosed in approximately one-fourth of individuals with congenital. The majority of patients with cochlear malformations remain etiologically undiagnosed due to insufficient knowledge about underlying genes or the inability to make conclusive interpretations of identified genetic variants. We used exome sequencing for the genetic evaluation of hearing loss associated with cochlear malformations in three probands from unrelated families deafness. We subsequently generated monoclonal induced pluripotent stem cell (iPSC) lines, bearing patient-specific knockins and knockouts using CRISPR/Cas9 to assess pathogenicity of candidate variants. We detected FGF3 (p.Arg165Gly) and GREB1L (p.Cys186Arg), variants of uncertain significance in two recognized genes for deafness, and PBXIP1(p.Trp574*) in a candidate gene. Upon differentiation of iPSCs towards inner ear organoids, we observed developmental aberrations in knockout lines compared to their isogenic controls. Patient-specific single nucleotide variants (SNVs) showed similar abnormalities as the knockout lines, functionally supporting their causality in the observed phenotype. Therefore, we present human inner ear organoids as a potential tool to validate the pathogenicity of DNA variants associated with cochlear malformations.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"375-389"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The genetic footprint of the European Roma diaspora: evidence from the Balkans to the Iberian Peninsula. 欧洲罗姆移民的基因足迹：从巴尔干到伊比利亚半岛的证据。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-04-01 Epub Date: 2025-03-17 DOI: 10.1007/s00439-025-02735-z

Giacomo Francesco Ena, Aaron Giménez, Annabel Carballo-Mesa, Petra Lišková, Marcos Araújo Castro E Silva, David Comas

{"title":"The genetic footprint of the European Roma diaspora: evidence from the Balkans to the Iberian Peninsula.","authors":"Giacomo Francesco Ena, Aaron Giménez, Annabel Carballo-Mesa, Petra Lišková, Marcos Araújo Castro E Silva, David Comas","doi":"10.1007/s00439-025-02735-z","DOIUrl":"10.1007/s00439-025-02735-z","url":null,"abstract":"The Roma people have a complex demographic history shaped by their recent dispersal from a South Asian origin into Europe, accompanied by continuous population bottlenecks and gene flow. After settling in the Balkans around 1,000 years ago, the Roma gradually dispersed across Europe, and approximately 500 years ago, they established in the Iberian Peninsula what is now one of the largest Roma populations in Western Europe. Focusing specifically on the Iberian Roma, we conducted the most comprehensive genome-wide analysis of European Roma populations to date. Using allele frequency and haplotype-based methods, we analysed 181 individuals to investigate their genetic diversity, social dynamics, and migration histories at both continental and local scales. Our findings demonstrate significant gene flow from populations encountered during the Roma's dispersal and confirm their South Asian origins. We show that, between the 14th and 19th centuries, the Roma spread westward from the Balkans in various waves, with multiple admixture events. Furthermore, our findings refute previous hypotheses of a North African dispersal route into Iberia and genetic connections to Jewish populations. The Iberian Roma exhibit ten times greater genetic differentiation compared to non-Roma Iberians, indicating significant regional substructure. Additionally, we provide the first genetic evidence of assortative mating within Roma groups, highlighting distinct mating patterns and suggesting a gradual shift towards increased integration with non-Roma individuals. This study significantly enhances our understanding of how demographic history and complex genetic structure have shaped the genetic diversity of Roma populations, while also highlighting the influence of their evolving social dynamics.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"463-479"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Global dysregulation of circular RNAs in frontal cortex and whole blood from DM1 and DM2. 额叶皮质和全血中DM1和DM2环状rna的全局失调。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-04-01 Epub Date: 2025-02-04 DOI: 10.1007/s00439-025-02729-x

Arvind Srinivasan, Dorota Magner, Piotr Kozłowski, Anna Philips, Arkadiusz Kajdasz, Paweł Wojciechowski, Marzena Wojciechowska

{"title":"Global dysregulation of circular RNAs in frontal cortex and whole blood from DM1 and DM2.","authors":"Arvind Srinivasan, Dorota Magner, Piotr Kozłowski, Anna Philips, Arkadiusz Kajdasz, Paweł Wojciechowski, Marzena Wojciechowska","doi":"10.1007/s00439-025-02729-x","DOIUrl":"10.1007/s00439-025-02729-x","url":null,"abstract":"Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular disorders associated with expansions of microsatellites, respectively, in DMPK and CNBP. Their pathogenesis is linked to the global aberrant alternative splicing (AAS) of many genes and marks mostly muscular and neuronal tissues, while blood is the least affected. Recent data in DM1 skeletal muscles indicated that abnormalities in RNA metabolism also include global upregulation of circular RNAs (circRNAs). CircRNAs are a heterogeneous group considered splicing errors and by-products of canonical splicing. To elucidate whether circRNA dysregulation is an inherent feature of the myotonic environment, we perform their analysis in the frontal cortex and whole blood of DM1 and DM2 patients. We find a global elevation of circRNAs in both tissues, and its magnitude is neither correlated with the differences in their parental gene expression nor is associated with AAS published earlier. Aberrantly spliced cassette exons of linear transcripts affected in DM1 and DM2 are not among the circularized exons, which unique genomic features prerequisite back-splicing. However, the blueprint of the AAS of linear RNAs is found in a variety of circRNA isoforms. The heterogeneity of circRNAs also originates from the utilization of exonic and intronic cryptic donors/acceptors in back splice junctions, and intron-containing circRNAs are more characteristic of the blood. Overall, this study reveals circRNA dysregulation in various tissues from DM1 and DM2; however, their levels do not correlate with the AAS in linear RNAs, suggesting a potential independent regulatory mechanism underlying circRNA upregulation in myotonic dystrophy.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"417-432"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Conventional and genetic association between migraine and stroke with druggable genome-wide Mendelian randomization. 偏头痛和中风与可用药全基因组孟德尔随机化之间的传统和遗传关联。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-04-01 Epub Date: 2025-01-22 DOI: 10.1007/s00439-024-02725-7

Xiaoyu Wang, Wendu Pang, Xin Hu, Tao Shu, Yaxin Luo, Junhong Li, Lan Feng, Ke Qiu, Yufang Rao, Yao Song, Minzi Mao, Yuyang Zhang, Jianjun Ren, Yu Zhao

{"title":"Conventional and genetic association between migraine and stroke with druggable genome-wide Mendelian randomization.","authors":"Xiaoyu Wang, Wendu Pang, Xin Hu, Tao Shu, Yaxin Luo, Junhong Li, Lan Feng, Ke Qiu, Yufang Rao, Yao Song, Minzi Mao, Yuyang Zhang, Jianjun Ren, Yu Zhao","doi":"10.1007/s00439-024-02725-7","DOIUrl":"10.1007/s00439-024-02725-7","url":null,"abstract":"The genetic relationship between migraine and stroke remains underexplored, particularly in the context of druggable targets. Previous studies have been limited by small sample sizes and a lack of focus on genetic-targeted therapies for these conditions. We analyzed the association and causality between migraine and stroke using multivariable logistic regression in the UK Biobank cohort and Mendelian randomization (MR) analyses based on genome-wide association study (GWAS) data. Integrating expression quantitative trait loci (eQTLs) data from blood and brain regions, we explored the phenotypic and genetic links between migraine medications, drug target, and stroke. Additionally, we explored novel druggable genes for migraine and evaluated their effects on migraine signaling molecules and stroke risk. Migraine was significantly associated with stroke, particularly ischemic stroke (IS) and intracerebral hemorrhage (ICH), with MR analysis confirming a causal link to ICH. HTR1A emerged as a potential link between antidepressants (preventive medications for migraine) and stroke. We identified 17 migraine-related druggable genes, with 5 genes (HMGCR, TGFB1, TGFB3, KCNK5, IMPDH2) associated with nine existing drugs. Further MR analysis identified correlation of CELSR3 and IMPDH2 with cGMP pathway marker PRKG1, and identified KCNK5, PLXNB1, and MDK as novel migraine-associated druggable genes significantly linked to the stroke risks. These findings established the phenotypic and genetic link between migraine, its medication and stroke, identifying potential targets for single and dual-purpose therapies for migraine and stoke, and emphasized the need for further research to validate these associations.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"391-404"},"PeriodicalIF":3.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0