Human molecular genetics最新文献_第10页

Neuromuscular junction transcriptome analysis of spinal and bulbar muscular atrophy mice implicates sarcomere gene expression and calcium flux dysregulation in disease pathogenesis. 脊髓和球性肌萎缩小鼠的神经肌肉连接转录组分析暗示了肌节基因表达和钙通量失调在疾病发病机制中的作用。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-07-03 DOI: 10.1093/hmg/ddaf074

Anastasia Gromova, Byeonggu Cha, Nhat Nguyen, Diya Garg, Connor Coscolluela, Laura M Strickland, David Luong, Fabiana Longo, Bryce L Sopher, Mai K ElMallah, Albert R La Spada

{"title":"Neuromuscular junction transcriptome analysis of spinal and bulbar muscular atrophy mice implicates sarcomere gene expression and calcium flux dysregulation in disease pathogenesis.","authors":"Anastasia Gromova, Byeonggu Cha, Nhat Nguyen, Diya Garg, Connor Coscolluela, Laura M Strickland, David Luong, Fabiana Longo, Bryce L Sopher, Mai K ElMallah, Albert R La Spada","doi":"10.1093/hmg/ddaf074","DOIUrl":"10.1093/hmg/ddaf074","url":null,"abstract":"X-linked Spinal and Bulbar Muscular Atrophy (SBMA) is a rare, late-onset neuromuscular disease caused by a CAG repeat expansion mutation in the androgen receptor (AR) gene. SBMA is characterized by progressive muscle atrophy of both neurogenic and myopathic etiologies. Previous work has established that mutant AR expression in skeletal muscle could be a significant contributor to neuromuscular decline, yet the mechanisms involved remain ill-defined. As AR is a nuclear hormone receptor transcription factor, we sought to define early changes in gene expression in skeletal muscle of pre-symptomatic SBMA mice, with a focus on transcriptional changes at the neuromuscular junction (NMJ). We describe loss of key NMJ-specific genes in synaptic muscle regions of pre-symptomatic SBMA mice, while extrasynaptic muscle features a coordinated loss of sarcomere genes that coincides with ectopic re-expression of certain NMJ genes. Furthermore, SBMA muscle prominently features dysregulated calcium flux, likely stemming from a compensatory response to early atrophy that greatly exacerbates over time. The SERCA activator CDN1163 conferred a mild rescue in function and muscle size in SBMA mice, while genetic deletion of the gene encoding Myf6/MRF4, a negative regulator of sarcomere gene expression and predicted AR interactor, did not ameliorate muscle atrophy. These studies suggest that modulation of calcium flux could be a promising pharmacological target in SBMA.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1238-1251"},"PeriodicalIF":3.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144077531","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

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 : 2025-07-03 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":"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":"1204-1215"},"PeriodicalIF":3.1,"publicationDate":"2025-07-03","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

Expression of Concern: Hippocampal phosphorylated tau induced cognitive decline, dendritic spine loss and mitochondrial abnormalities in a mouse model of Alzheimer's disease. 关注表达：海马磷酸化tau诱导阿尔茨海默病小鼠模型的认知能力下降、树突状脊柱丢失和线粒体异常。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-07-03 DOI: 10.1093/hmg/ddaf098

引用次数: 0

Editor's Note to: Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation. 编者注：考登综合征相关的种系sddd变异通过src诱导的PTEN氧化改变PTEN核易位。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-06-18 DOI: 10.1093/hmg/ddaf086

引用次数: 0

Correction to: Ubiquitin specific protease-13 independently regulates parkin ubiquitination and alpha-synuclein clearance in alpha-synucleinopathies. 修正：泛素特异性蛋白酶-13在α -突触核蛋白病中独立调节帕金泛素化和α -突触核蛋白清除。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-18 DOI: 10.1093/hmg/ddaf078

引用次数: 0

UNRAVELING CLN7 disease: the distinct roles of two close MFSD8/CLN7 splice variants in phenotypic expression. 揭示CLN7疾病：两个相近的MFSD8/CLN7剪接变体在表型表达中的不同作用

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-18 DOI: 10.1093/hmg/ddaf067

Ana Clara Venier, Sofía Savy, Gerardo Carro, Guillermo Guelbert, Ezequiel Grondona, Norberto Guelbert, Juan Pablo Nicola, Favio Pesaola, Ana Lucía De Paul

{"title":"UNRAVELING CLN7 disease: the distinct roles of two close MFSD8/CLN7 splice variants in phenotypic expression.","authors":"Ana Clara Venier, Sofía Savy, Gerardo Carro, Guillermo Guelbert, Ezequiel Grondona, Norberto Guelbert, Juan Pablo Nicola, Favio Pesaola, Ana Lucía De Paul","doi":"10.1093/hmg/ddaf067","DOIUrl":"10.1093/hmg/ddaf067","url":null,"abstract":"CLN7 is a lysosomal storage disease caused by pathogenic variants in the MFSD8/CLN7 gene. Typically neurodegenerative, patients present seizures and developmental delay since 2-6 years of age and a rapid psychomotor, verbal, and visual deterioration that leads to premature death. However, 'atypical' cases have also been reported. Although more than 80 DNA variants in the MFSD8/CLN7 gene have been reported, no data about a genotype/phenotype correlation is available. Here, we analyze five 'classical' and 'atypical' CLN7 patients by molecular and computational methods. Four variants have been found: c.103C > T (p.Arg35*, pathogenic), c.1394G > A (p.Arg465Gln, pathogenic), c.863 + 1G > A (likely pathogenic), and c.863 + 4A > G (of uncertain significance). Both splice variants showed altering of the splicing process on a minigene reporter assay. Furthermore, exon 8 was deleted in the MFSD8/CLN7 cDNA of blood samples from two patients carrying the splicing variants, demonstrating their effect. The c.863 + 4A > G variant also showed a residual wildtype MFSD8/CLN7 expression and, thus, explaining the milder phenotype. Finally, a clustered geographical distribution of the c.103C > T and c.863 + 4A > G variants was observed in the northeast and center of Argentina, respectively. Our data confirm the pathogenicity of the c.863 + 1G > A variant and reclassify the c.863 + 4A > G variant as pathogenic by adding experimental data, offering new information for a precise prognosis, and expanding the genetic and epidemiological spectrum of CLN7 in the South American region. Ultimately, we seek to raise awareness about the existence of this pathology in the region to reduce the so-called 'diagnostic odyssey' in pediatric patients.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1157-1167"},"PeriodicalIF":3.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002128","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

Transcriptional reprogramming in SMA mouse hearts reveals signatures of early heart failure and dysregulated calcium signaling. SMA小鼠心脏的转录重编程揭示了早期心力衰竭和钙信号失调的特征。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-18 DOI: 10.1093/hmg/ddaf060

Cecelia C Mangione, Andrew Frank, Clifton L Dalgard, Barrington G Burnett, Thomas P Flagg

{"title":"Transcriptional reprogramming in SMA mouse hearts reveals signatures of early heart failure and dysregulated calcium signaling.","authors":"Cecelia C Mangione, Andrew Frank, Clifton L Dalgard, Barrington G Burnett, Thomas P Flagg","doi":"10.1093/hmg/ddaf060","DOIUrl":"10.1093/hmg/ddaf060","url":null,"abstract":"Spinal muscular atrophy (SMA) is an inherited neurodegenerative disease that leads to loss of motor neurons in the anterior horn of the spinal cord with consequent muscle atrophy. SMA results from the functional deletions of the SMN1 gene, resulting in insufficient production of the survival motor neuron (SMN) protein. It is not known why lower motor neurons are particularly sensitive to the loss of SMN function, but it is increasingly apparent that extraneuronal tissues, such as cardiac and skeletal muscle, are also affected by SMN deficiency. We have previously shown that SMN deficiency in a mouse model of spinal muscular atrophy (SMNΔ7) impairs cardiomyocyte contraction and Ca2+ handling. In this study, we performed a comparative total mRNA sequencing analysis of whole hearts isolated at an early (P5) or late (P10) stage of the disease process to investigate the mechanisms contributing to cardiac pathology in SMA. The results demonstrate transcriptional signatures consistent with heart failure, dysregulation of Ca2+ signaling, and hypoxia induced changes occurring as early as P5 and persisting through P10. Similar transcriptomic changes in skeletal muscle tissue indicate that there are likely common, cell autonomous molecular mechanisms resulting in both cardiac and skeletal muscle due to SMN deficiency. The identification of these common themes suggests a link underlying the mechanism of neuronal and non-neuronal deficits in SMA.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1123-1133"},"PeriodicalIF":3.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12199365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970035","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

Kinetin mediated mutant huntingtin phosphorylation restores multiple dysregulated pathways in a cell line model of Huntington's disease. 在亨廷顿病细胞系模型中，激动素介导的突变亨廷顿蛋白磷酸化恢复了多种失调的途径。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-18 DOI: 10.1093/hmg/ddaf052

Rajubhai Dabhi, Ragi Mehta, Dhruvi Kakadiya, Ravi Vijayvargia

{"title":"Kinetin mediated mutant huntingtin phosphorylation restores multiple dysregulated pathways in a cell line model of Huntington's disease.","authors":"Rajubhai Dabhi, Ragi Mehta, Dhruvi Kakadiya, Ravi Vijayvargia","doi":"10.1093/hmg/ddaf052","DOIUrl":"10.1093/hmg/ddaf052","url":null,"abstract":"Huntington's disease (HD) is a fatal neurodegenerative disease caused by CAG trinucleotide repeat expansion in the huntingtin gene (Htt) resulting in an expanded polyglutamine (polyQ) tract in the huntingtin (HTT) protein. The expanded polyQ alters structure of HTT making it susceptible to aggregation. The expression of mutant HTT (mHTT) causes dysregulation of several key cellular pathways in neuronal cells resulting in neurodegeneration. Recent studies have demonstrated phosphorylation of the N-terminal domain of the huntingtin (N-HTT) protein as an important regulator of its localization, structure, aggregation, clearance and toxicity. Most studies have focused on the effect of phosphorylation of Ser13 and Ser16 in N-HTT on protein aggregation and reported a drastic reduction in aggregation. However, the downstream impact of this phosphorylation status on key cellular pathways is largely unexplored. Utilizing an inducible cell line model for expression of Exon 1 fragment of mHTT bearing 150 polyglutamine repeats (HD150Q), we demonstrate that kinetin induced phosphorylation at Ser13 and Ser16 of N-HTT resulted in prevention of aggregation as well as resolution of preformed aggregates. Furthermore, kinetin treatment led to rescue of ATP levels and transcription of key genes as well as significant reduction in mitochondrial ROS levels restoring mitochondrial function. Notably, ER stress markers were significantly reduced at transcriptional, translational and post-translational levels. Restoration of mitochondrial function and mitigation of ER stress lead to significant improvement in cell survival. These findings further strengthen the view that HTT N-terminal phosphorylation is a promising therapeutic target for HD.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1097-1107"},"PeriodicalIF":3.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018413","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

Defective IFT57 underlies a novel cause of Bardet-Biedl syndrome. IFT57缺陷是Bardet-Biedl综合征的新病因。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-18 DOI: 10.1093/hmg/ddaf058

Alexandra Nitoiu, Qihong Zhang, Erika Tavares, Janice Min Li, Kashif Ahmed, Kit Green-Sanderson, Mahnoor Rashid, Shahir M Morcos, Jayson T Maynes, Eric I Campos, Val C Sheffield, Ajoy Vincent, Elise Héon

{"title":"Defective IFT57 underlies a novel cause of Bardet-Biedl syndrome.","authors":"Alexandra Nitoiu, Qihong Zhang, Erika Tavares, Janice Min Li, Kashif Ahmed, Kit Green-Sanderson, Mahnoor Rashid, Shahir M Morcos, Jayson T Maynes, Eric I Campos, Val C Sheffield, Ajoy Vincent, Elise Héon","doi":"10.1093/hmg/ddaf058","DOIUrl":"10.1093/hmg/ddaf058","url":null,"abstract":"A 29-year-old male presented with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome (BBS). Following negative clinical genetic testing, genome analysis identified biallelic variants in IFT57: p.(Val397Glu) and p.(Lys225Asnfs*17). IFT57 is part of complex B of the intraflagellar transport (IFT) proteins, which is an adaptor to the anterograde transport of proteins, bringing cargo from the base of the primary cilia to the tip. Variants in IFT57 have not yet been associated with BBS or human retinal degeneration, but biallelic splicing variants were associated with a distinct ciliopathy: oral-facial-digital syndrome. Using patient-derived fibroblasts, IFT57-knockouts (KO) of RPE1, and mIMCD3 cells, we showed that p.(Lys225Asnfs*17) is subjected to non-sense mediated decay, and that p.(Val397Glu) is the predominant variant which leads to cilia defects. Exogenous expression of the p.(Val397Glu) variant partially restored structural and functional primary cilia defects, and of the anterograde transport in Ift57-KO mIMCD3 cells but it did not rescue primary cilia in retinal IFT57-KO-RPE1 cells. The cell autonomous effect, likely explains the retinal dystrophy in our proband with BBS.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1108-1122"},"PeriodicalIF":3.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12199350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984476","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

Loss of Nup160 dysregulates Cdc42 in the podocytes of podocyte-specific Nup160 knockout mice. 缺失Nup160会导致足细胞特异性Nup160敲除小鼠足细胞中的Cdc42失调。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-18 DOI: 10.1093/hmg/ddaf064

Deying Liu, Jiaxin Li, Chan Xu, Yuanyuan Li, Xiaohan Chen, Feng Zhao, Huajuan Tong, Yonghui Yang, Xiaojian Qiu, Zihua Yu

{"title":"Loss of Nup160 dysregulates Cdc42 in the podocytes of podocyte-specific Nup160 knockout mice.","authors":"Deying Liu, Jiaxin Li, Chan Xu, Yuanyuan Li, Xiaohan Chen, Feng Zhao, Huajuan Tong, Yonghui Yang, Xiaojian Qiu, Zihua Yu","doi":"10.1093/hmg/ddaf064","DOIUrl":"10.1093/hmg/ddaf064","url":null,"abstract":"Mutations in four genes encoding the outer ring complex of nuclear pore complexes (NPCs), NUP85, NUP107, NUP133 and NUP160, cause monogenic steroid-resistant nephrotic syndrome (SRNS). Knockout of NUP85, NUP107, or NUP133 in immortalized human podocytes activates CDC42, an important effector of SRNS pathogenesis. However, it is unknown whether or not loss of NUP160 dysregulates CDC42 in the podocytes. Here, we generated a podocyte-specific Nup160 knockout mouse model with double-fluorescent (mT/mG) Cre reporter genes using CRISPR/Cas9 and Cre/loxP technologies. We investigated nephrotic syndrome-associated phenotypes in the Nup160podo-/- mice, and performed single-cell transcriptomic and proteomic analysis of glomerular suspension cells and cultured primary podocytes, respectively. The Nup160podo-/- mice exhibited progressive proteinuria and fusion of podocyte foot processes. We found decreased Cdc42 protein and normal Cdc42 transcriptional level in the podocytes of the Nup160podo-/- mice using analysis of single-cell transcriptomes and proteomes. We subsequently observed that Cdc42 protein decreased in both kidney tissues and cultured primary podocytes of the Nup160podo-/- mice, although Cdc42 mRNA levels were elevated in the cultured primary podocytes of the Nup160podo-/- mice. We also found that Cdc42 activity was significantly reduced in the cultured primary podocytes of the Nup160podo-/- mice. In conclusion, loss of Nup160 dysregulated Cdc42 in the podocytes of the Nup160podo-/- mice with proteinuria and fusion of podocyte foot processes. Our findings suggest that the dysregulation of CDC42 may contribute to the pathogenesis of SRNS in patients with mutations in NUP160.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1134-1145"},"PeriodicalIF":3.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998583","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