Human molecular genetics最新文献_第4页

Functional characterization of OXTR-associated enhancers. oxtr相关增强子的功能表征。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-05-06 DOI: 10.1093/hmg/ddaf022

Dianne Laboy Cintrón, Rory R Sheng, Nadav Ahituv

引用次数: 0

Aggregates associated with amyotrophic lateral sclerosis sequester the actin-binding protein profilin 2. 与肌萎缩性侧索硬化症相关的聚集体隔离肌动蛋白结合蛋白2。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-05-06 DOI: 10.1093/hmg/ddaf020

Sabrina Kubinski, Luisa Claus, Tobias Schüning, Andre Zeug, Norman Kalmbach, Selma Staege, Thomas Gschwendtberger, Susanne Petri, Florian Wegner, Peter Claus, Niko Hensel

{"title":"Aggregates associated with amyotrophic lateral sclerosis sequester the actin-binding protein profilin 2.","authors":"Sabrina Kubinski, Luisa Claus, Tobias Schüning, Andre Zeug, Norman Kalmbach, Selma Staege, Thomas Gschwendtberger, Susanne Petri, Florian Wegner, Peter Claus, Niko Hensel","doi":"10.1093/hmg/ddaf020","DOIUrl":"10.1093/hmg/ddaf020","url":null,"abstract":"Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of upper and lower motoneurons. The four most frequently mutated genes causing familial ALS (fALS) are C9orf72, FUS, SOD1, and TARDBP. Some of the related wild-type proteins comprise intrinsically disordered regions (IDRs) which favor their assembly in liquid droplets-the biophysical mechanism behind the formation of physiological granules such as stress granules (SGs). SGs assemble and dissolve dependent on the cellular condition. However, it has been suggested that transition from reversible SGs to irreversible aggregates contributes to the toxic properties of ALS-related mutated proteins. Sequestration of additional proteins within these aggregates may then result in downstream toxicity. While the exact downstream mechanisms remain elusive, rare ALS-causing mutations in the actin binding protein profilin 1 suggest an involvement of the actin cytoskeleton. Here, we hypothesize that profilin isoforms become sequestered in aggregates of ALS-associated proteins which induce subsequent dysregulation of the actin cytoskeleton. Interestingly, localization of neuronal profilin 2 in SGs was more pronounced compared with the ubiquitously expressed profilin 1. Accordingly, FUS and C9orf72 aggregates prominently sequestered profilin 2 but not profilin 1. Moreover, we observed a distinct sequestration of profilin 2 and G-actin to C9orf72 aggregates in different cellular models. On the functional level, we identified dysregulated actin dynamics in cells with profilin 2-sequestering aggregates. In summary, our results suggest a more common involvement of profilins in ALS pathomechanisms than indicated from the rarely occurring profilin mutations.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"882-893"},"PeriodicalIF":3.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596768","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

Rare DCM associated variants in pre-miR-208a disrupt miRNA maturation and function. pre-miR-208a中罕见的DCM相关变异会破坏miRNA的成熟和功能。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-05-06 DOI: 10.1093/hmg/ddaf069

Yolan J Reckman, Jan Haas, Ingeborg van der Made, Simon G Williams, Iria Gomez Diaz, Mohammed Akhtar, Jens Mogensen, Torsten B Rasmussen, Eric Villard, Philippe Charron, Perry Elliott, Bernard D Keavney, Lorenzo Monserrat, Yigal M Pinto, Benjamin Meder, Anke J Tijsen

{"title":"Rare DCM associated variants in pre-miR-208a disrupt miRNA maturation and function.","authors":"Yolan J Reckman, Jan Haas, Ingeborg van der Made, Simon G Williams, Iria Gomez Diaz, Mohammed Akhtar, Jens Mogensen, Torsten B Rasmussen, Eric Villard, Philippe Charron, Perry Elliott, Bernard D Keavney, Lorenzo Monserrat, Yigal M Pinto, Benjamin Meder, Anke J Tijsen","doi":"10.1093/hmg/ddaf069","DOIUrl":"https://doi.org/10.1093/hmg/ddaf069","url":null,"abstract":"Dilated cardiomyopathy (DCM) is a major cause of heart failure (HF) defined by ventricular dilatation and systolic dysfunction. Although microRNAs (miRNAs) are known to affect HF development, little is known about the contribution of genetic variants in miRNAs or their precursors to the susceptibility or pathogenesis of DCM. We screened 1640 DCM cases for variants in cardiac miR-208a and miR-208b and their precursors. We identified four variants in the miR-208a pre-miRNA, which are present at very low frequencies in the general population. Two of these variants (+42G > T and +68G > T) alter a highly conserved nucleotide and the predicted pre-miRNA secondary structure. Both variants result in reduced mature miR-208a levels in overexpression experiments. The variant +42G > T also increased pre-miR-208a levels in these experiments, which indicates a maturation deficiency. Co-transfection of the overexpression constructs with a luciferase construct containing six miRNA binding sites revealed that both variants also impair repression of luciferase expression by miR-208a, indicative of also a loss of miR208a function. Together this indicates that these DCM-associated variants impair formation of mature miR208a. Combined with the role of miR-208a in cardiac contractility this suggests that variants +42G > T and +68G > T in pre-miR-208a may contribute to the DCM phenotype observed in these patients.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063521","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

Correction to: A combinatorial approach increases SMN level in SMA model mice. 修正：组合方法增加SMA模型小鼠的SMN水平。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-05-06 DOI: 10.1093/hmg/ddaf073

引用次数: 0

Synaptic defects in adult drosophila motor neurons in a model of amyotrophic lateral sclerosis. 肌萎缩侧索硬化症模型中成年果蝇运动神经元的突触缺陷。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-05-06 DOI: 10.1093/hmg/ddaf068

Tulika Malik, Jessica M Sidisky, Sam Jones, Alexander Winters, Brandon Hocking, Jocelyn Rotay, Ellen N Huhulea, Sara Moran, Bali Connors, Daniel T Babcock

{"title":"Synaptic defects in adult drosophila motor neurons in a model of amyotrophic lateral sclerosis.","authors":"Tulika Malik, Jessica M Sidisky, Sam Jones, Alexander Winters, Brandon Hocking, Jocelyn Rotay, Ellen N Huhulea, Sara Moran, Bali Connors, Daniel T Babcock","doi":"10.1093/hmg/ddaf068","DOIUrl":"https://doi.org/10.1093/hmg/ddaf068","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons in the brain and spinal cord. Like other neurodegenerative diseases, defects in synaptic integrity are among the earliest hallmarks of ALS. However, the specific impairments to synaptic integrity remain unclear. To better understand synaptic defects in ALS, we expressed either wild-type or mutant Fused in Sarcoma (FUS), an RNA binding protein that is often mis-localized in ALS, in adult motor neurons. Using optogenetic stimulation of the motor neurons innervating the Ventral Abdominal Muscles (VAMs), we found that expression of mutant FUS disrupted the functional integrity of these synapses. This functional deficit was followed by disruption of synaptic gross morphology, localization of pre- and post-synaptic proteins, and cytoskeleton integrity. We found similar synaptic defects using the motor neurons innervating the Dorsal Longitudinal Muscles (DLMs), where expression of mutant FUS resulted in a progressive loss of flight ability along with disruption of active zone distribution. Our findings uncover defects in synaptic function that precede changes in synaptic structure, suggesting that synaptic function is more sensitive to this ALS model. Highlighting the earliest synaptic defects in this disease model should help to identify strategies for preventing later stages of disease progression.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965179","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

Correction to: Testing the PEST hypothesis using relevant Rett mutations in MeCP2 E1 and E2 isoforms. 更正：使用MeCP2 E1和E2亚型的相关Rett突变来检验PEST假说。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-05-05 DOI: 10.1093/hmg/ddaf072

引用次数: 0

The modifying effect of mutant LRRK2 on mutant GBA1-associated Parkinson disease. 突变体LRRK2对突变体gba1相关帕金森病的修饰作用

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-05-02 DOI: 10.1093/hmg/ddaf062

Serebryany-Piavsky Vera, Egulsky Lian, Manoim-Wolkovitz Julia Elia, Anis Saar, Hassin-Baer Sharon, Parnas Moshe, Horowitz Mia

{"title":"The modifying effect of mutant LRRK2 on mutant GBA1-associated Parkinson disease.","authors":"Serebryany-Piavsky Vera, Egulsky Lian, Manoim-Wolkovitz Julia Elia, Anis Saar, Hassin-Baer Sharon, Parnas Moshe, Horowitz Mia","doi":"10.1093/hmg/ddaf062","DOIUrl":"https://doi.org/10.1093/hmg/ddaf062","url":null,"abstract":"Parkinson disease (PD) is the second most common neurodegenerative disease. While most cases are sporadic, in ~ 5%-10% of PD patients the disease is caused by mutations in several genes, among them GBA1 (glucocerebrosidase beta 1) and LRRK2 (leucine-rich repeat kinase 2), both prevalent among the Ashkenazi Jewish population. LRRK2-associated PD tends to be milder than GBA1-associated PD. Several recent clinical studies have suggested that carriers of both GBA1 and LRRK2 mutations develop milder PD compared to that observed among GBA1 carriers. These findings strongly suggested an interplay between the two genes in the development and progression of PD. In the present study Drosophila was employed as a model to investigate the impact of mutations in the LRRK2 gene on mutant GBA1-associated PD. Our results strongly indicated that flies expressing both mutant genes exhibited milder parkinsonian signs compared to the disease developed in flies expressing only a GBA1 mutation. This was corroborated by a decrease in the ER stress response, increase in the number of dopaminergic cells, elevated levels of tyrosine hydroxylase, reduced neuroinflammation, improved locomotion and extended survival. Furthermore, a significant decrease in the steady-state levels of mutant GBA1-encoded GCase was observed in the presence of mutant LRRK2, strongly implying a role for mutant LRRK2 in degradation of mutant GCase.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968268","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

Diverse landscape of genomic research within the Estonian Biobank. 爱沙尼亚生物库内基因组研究的多样化景观。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-05-02 DOI: 10.1093/hmg/ddaf026

Reedik Mägi

引用次数: 0

Expanding scope of genetic studies in the era of biobanks. 在生物银行时代，基因研究的范围不断扩大。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-05-02 DOI: 10.1093/hmg/ddaf054

Diptavo Dutta, Nilanjan Chatterjee

{"title":"Expanding scope of genetic studies in the era of biobanks.","authors":"Diptavo Dutta, Nilanjan Chatterjee","doi":"10.1093/hmg/ddaf054","DOIUrl":"https://doi.org/10.1093/hmg/ddaf054","url":null,"abstract":"Biobanks have become pivotal in genetic research, particularly through genome-wide association studies (GWAS), driving transformative insights into the genetic basis of complex diseases and traits through the integration of genetic data with phenotypic, environmental, family history, and behavioral information. This review explores the distinct design and utility of different biobanks, highlighting their unique contributions to genetic research. We further discuss the utility and methodological advances in combining data from disease-specific study or consortia with that of biobanks, especially focusing on summary statistics based meta-analysis. Subsequently we review the spectrum of additional advantages offered by biobanks in genetic studies in representing population differences, calibration of polygenic scores, assessment of pleiotropy and improving post-GWAS in silico analyses. Advances in sequencing technologies, particularly whole-exome and whole-genome sequencing, have further enabled the discovery of rare variants at biobank scale. Among recent developments, the integration of large-scale multi-omics data especially proteomics and metabolomics, within biobanks provides deeper insights into disease mechanisms and regulatory pathways. Despite challenges like ascertainment strategies and phenotypic misclassification, biobanks continue to evolve, driving methodological innovation and enabling precision medicine. We highlight the contributions of biobanks to genetic research, their growing integration with multi-omics, and finally discuss their future potential for advancing healthcare and therapeutic development.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998551","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 and pathogen-encoded circular RNAs in viral infections: insights into functions and therapeutic opportunities. 病毒感染中的人类和病原体编码环状rna：对功能和治疗机会的见解。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-04-30 DOI: 10.1093/hmg/ddaf031

Noah L Mueller, Adela Dujsikova, Amrita Singh, Y Grace Chen

{"title":"Human and pathogen-encoded circular RNAs in viral infections: insights into functions and therapeutic opportunities.","authors":"Noah L Mueller, Adela Dujsikova, Amrita Singh, Y Grace Chen","doi":"10.1093/hmg/ddaf031","DOIUrl":"https://doi.org/10.1093/hmg/ddaf031","url":null,"abstract":"Circular RNAs (circRNAs) are emerging as important regulatory molecules in both host and viral systems, acting as microRNA sponges, protein decoys or scaffolds, and templates for protein translation. Host-derived circRNAs are increasingly recognized for their roles in immune responses, while virus-encoded circRNAs, especially those from DNA viruses, have been shown to modulate host cellular machinery to favor viral replication and immune evasion. Recently, RNA virus-encoded circRNAs were also discovered, but evidence suggests that they might be generated using a different mechanism compared to the circRNAs produced from the host and DNA viruses. This review highlights recent advances in our understanding of both host and virus-derived circRNAs, with a focus on their biological roles and contributions to pathogenesis. Furthermore, we discuss the potential of circRNAs as biomarkers and their application as therapeutic targets or scaffolds for RNA-based therapies. Understanding the roles of circRNAs in host-virus interactions offers novel insights into RNA biology and opens new avenues for therapeutic strategies against viral diseases and associated cancers.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994960","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