Human molecular genetics最新文献

Deregulated ion channels contribute to RHOBTB2-associated developmental and epileptic encephalopathy.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-01-24 DOI: 10.1093/hmg/ddae183

Franziska Langhammer, Anne Gregor, Niels R Ntamati, Arif B Ekici, Beate Winner, Thomas Nevian, Christiane Zweier

{"title":"Deregulated ion channels contribute to RHOBTB2-associated developmental and epileptic encephalopathy.","authors":"Franziska Langhammer, Anne Gregor, Niels R Ntamati, Arif B Ekici, Beate Winner, Thomas Nevian, Christiane Zweier","doi":"10.1093/hmg/ddae183","DOIUrl":"https://doi.org/10.1093/hmg/ddae183","url":null,"abstract":"While de novo missense variants in the BTB domains of atypical RhoGTPase RHOBTB2 cause a severe developmental and epileptic encephalopathy, de novo missense variants in the GTPase domain or bi-allelic truncating variants are associated with more variable neurodevelopmental and seizure phenotypes. Apart from the observation of RHOBTB2 abundance resulting from BTB-domain variants and increased seizure susceptibility in Drosophila overexpressing RhoBTB, our knowledge on RHOBTB2-related pathomechanisms is limited. We now found enrichment for ion channels among the differentially expressed genes from RNA-Seq on fly heads overexpressing RhoBTB. Subsequent genetic interaction experiments confirmed a functional link between RhoBTB and paralytic, the orthologue of human sodium channels, including epilepsy associated SCN1A, in vivo. We then performed patch-clamp recordings on mature neurons differentiated from human induced pluripotent stem cells with either homozygous frameshifts or patient-specific heterozygous missense variants in the GTPase or the BTB domains. This revealed significantly altered neuronal activity and excitability resulting from BTB domain variants but not from GTPase domain variants or upon complete loss of RHOBTB2. Our study indicates a role of deregulated ion channels in the pathogenesis of RHOBTB2-related developmental and epileptic encephalopathy and points to specific pathomechanisms underlying the observed genotype-phenotype correlations regarding variant zygosity, location and nature.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028642","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

A novel frameshift mutation of SOX10 identified in Waardenburg syndrome type 2.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-01-24 DOI: 10.1093/hmg/ddaf010

Wenqing Han, Run Yang, Xin Chen, Ying Chen, Tianyu Zhang, Jing Ma

引用次数: 0

Genetic analysis implicates ERAP1 and HLA as risk factors for severe Puumala virus infection. 遗传分析表明，ERAP1 和 HLA 是严重 Puumala 病毒感染的风险因素。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-01-23 DOI: 10.1093/hmg/ddae158

Hele Haapaniemi, Satu Strausz, Anniina Tervi, Samuel E Jones, Mari Kanerva, Erik Abner, Anne-Marie Fors Connolly, Hanna M Ollila

{"title":"Genetic analysis implicates ERAP1 and HLA as risk factors for severe Puumala virus infection.","authors":"Hele Haapaniemi, Satu Strausz, Anniina Tervi, Samuel E Jones, Mari Kanerva, Erik Abner, Anne-Marie Fors Connolly, Hanna M Ollila","doi":"10.1093/hmg/ddae158","DOIUrl":"10.1093/hmg/ddae158","url":null,"abstract":"Puumala virus (PUUV) infections can cause severe illnesses such as Hemorrhagic Fever with Renal Syndrome in humans. However, human genetic risk factors contributing to disease severity are still poorly understood. Our goal was to elucidate genetic factors contributing to PUUV infections and understand the biological mechanisms underlying individual vulnerability to PUUV infections. Leveraging data from the FinnGen study, we conducted a genome-wide association study on severe Hemorrhagic Fever with Renal Syndrome caused by PUUV with 2227 cases. We identified associations at the Human Leukocyte Antigen (HLA) locus and ERAP1 with severe PUUV infection. HLA molecules are canonical mediators for immune recognition and response. ERAP1 facilitates immune system recognition and activation by cleaving viral proteins into smaller peptides which are presented to the immune system via HLA class I molecules. Notably, we identified that the lead variant (rs26653, OR = 0.84, P = 2.9 × 10-8) in the ERAP1 gene was a missense variant changing amino acid arginine to proline. From the HLA region, we showed independent and significant associations with both HLA class I and II genes. Furthermore, we showed independent associations with four HLA alleles with severe PUUV infection using conditional HLA fine mapping. The strongest association was found with the HLA-C*07:01 allele (OR = 1.54, P = 4.0 × 10-24) followed by signals at HLA-B*13:02, HLA-DRB1*01:01, and HLA-DRB1*11:01 alleles (P < 5 × 10-8). Our findings suggest an association of viral peptide processing with ERAP1 and antigen presentation through HLA alleles that may contribute to the development of severe PUUV disease.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"77-84"},"PeriodicalIF":3.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619288","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

Analysis of genotype effects and inter-individual variability in iPSC-derived trisomy 21 neural progenitor cells. 分析 iPSC 衍生的 21 三体综合征神经祖细胞的基因型效应和个体间差异。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-01-23 DOI: 10.1093/hmg/ddae160

Sarah E Lee, Laura L Baxter, Monica I Duran, Samuel D Morris, Iman A Mosley, Kevin A Fuentes, Jeroen L A Pennings, Faycal Guedj, Diana W Bianchi

{"title":"Analysis of genotype effects and inter-individual variability in iPSC-derived trisomy 21 neural progenitor cells.","authors":"Sarah E Lee, Laura L Baxter, Monica I Duran, Samuel D Morris, Iman A Mosley, Kevin A Fuentes, Jeroen L A Pennings, Faycal Guedj, Diana W Bianchi","doi":"10.1093/hmg/ddae160","DOIUrl":"10.1093/hmg/ddae160","url":null,"abstract":"Trisomy of human chromosome 21 (T21) gives rise to Down syndrome (DS), the most frequent live-born autosomal aneuploidy. T21 triggers genome-wide transcriptomic alterations that result in multiple atypical phenotypes with highly variable penetrance and expressivity in individuals with DS. Many of these phenotypes, including atypical neurodevelopment, emerge prenatally. To enable in vitro analyses of the cellular and molecular mechanisms leading to the neurological alterations associated with T21, we created and characterized a panel of genomically diverse T21 and euploid induced pluripotent stem cells (iPSCs). We subsequently differentiated these iPSCs to generate a panel of neural progenitor cells (NPCs). Alongside characterizing genotype effects from T21, we found that T21 NPCs showed inter-individual variability in growth rates, oxidative stress, senescence characteristics, and gene and protein expression. Pathway enrichment analyses of T21 NPCs identified vesicular transport, DNA repair, and cellular response to stress pathways. These results demonstrate T21-associated variability at the cellular level and suggest that cell lines from individuals with DS should not solely be analyzed as a homogenous population. Examining large cohorts of genetically diverse samples may more fully reveal the effects of aneuploidy on transcriptomic and phenotypic characteristics in T21 cell types. A panel of genomically diverse T21 and euploid induced pluripotent stem cells (iPSCs) were created and subsequently differentiated into neural progenitor cells (NPCs). T21 NPCs showed reduced growth, increased oxidative stress, and inter-individual variability in gene and protein expression. This inter-individual variability suggests that studies with large cohorts of genetically diverse T21 samples may more fully reveal the effects of aneuploidy.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"85-100"},"PeriodicalIF":3.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619279","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

Alternative polyadenylation shapes the molecular and clinical features of lung adenocarcinoma. 交替多腺苷酸化决定了肺腺癌的分子和临床特征。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-01-23 DOI: 10.1093/hmg/ddae150

Yipeng Gao, Vikram R Shaw, Christopher I Amos

{"title":"Alternative polyadenylation shapes the molecular and clinical features of lung adenocarcinoma.","authors":"Yipeng Gao, Vikram R Shaw, Christopher I Amos","doi":"10.1093/hmg/ddae150","DOIUrl":"10.1093/hmg/ddae150","url":null,"abstract":"Alternative polyadenylation (APA) is a major mechanism of post-transcriptional regulation that affects mRNA stability, localization and translation efficiency. Previous pan-cancer studies have revealed that APA is frequently disrupted in cancer and is associated with patient outcomes. Yet, little is known about cancer type-specific APA alterations. Here, we integrated RNA-sequencing data from a Korean cohort (GEO: GSE40419) and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA alterations in lung adenocarcinomas (LUADs). Comparing expression levels of core genes involved in polyadenylation, we find that overall, the set of 28 of 31 genes are upregulated, with CSTF2 particularly upregulated. We observed broad and recurrent APA changes in LUAD growth-promoting genes. In addition, we find enrichment of APA events in genes associated with known LUAD pathways and an increased heterogeneity in polyadenylation (polyA) site usage of proliferation-associated genes. Upon further investigation, we report smoking-specific APA changes are also highly relevant to LUAD development. Overall, our in-depth analysis reveals APA as an important driver for the molecular and clinical features of lung adenocarcinoma.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1-10"},"PeriodicalIF":3.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564377","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

Characterisation of LGP2 complex multitranscript system in humans: role in the innate immune response and evolution from non-human primates. 人类 LGP2 复合多转录本系统的特征：在先天性免疫反应中的作用以及与非人灵长类动物的进化。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-01-23 DOI: 10.1093/hmg/ddae155

Jorge Martinez-Laso, Isabel Cervera, Marina S Martinez-Carrasco, Veronica Briz, Celia Crespo-Bermejo, Clara Sánchez-Menéndez, Guiomar Casado-Fernández, Montserrat Torres, Mayte Coiras

{"title":"Characterisation of LGP2 complex multitranscript system in humans: role in the innate immune response and evolution from non-human primates.","authors":"Jorge Martinez-Laso, Isabel Cervera, Marina S Martinez-Carrasco, Veronica Briz, Celia Crespo-Bermejo, Clara Sánchez-Menéndez, Guiomar Casado-Fernández, Montserrat Torres, Mayte Coiras","doi":"10.1093/hmg/ddae155","DOIUrl":"10.1093/hmg/ddae155","url":null,"abstract":"Retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), including RIG-I, MDA5 and LGP2, recognize viral RNA to mount an antiviral interferon (IFN) response RLRs share three different protein domains: C-terminal domain, DExD/H box RNA helicase domain, and an N-terminal domain with two tandem repeats (CARDs). LGP2 lacks tandem CARD and is not able to induce an IFN response. However, LGP2 positively enhances MDA5 and negatively regulates RIG-I signaling. In this study, we determined the LGP2 alternative transcripts in humans to further comprehend the mechanism of its regulation, their evolutionary origin, and the isoforms functionallity. The results showed new eight alternative transcripts in the samples tested. The presence of these transcripts demonstrated that the main mechanisms for the regulation of LGP2 expression are both by insertion of introns and by the loss of exons. The phylogenetic analysis of the comparison between sequences from exon 1 to exon 3 of humans and those previously described in non-human primates showed three well-differentiated groups (lineages) originating from gorillas, suggesting that the transspecies evolution has been maintained for 10 million years. The corresponding protein models (isoforms) were also established, obtaining four isoforms: one complete and three others lacking the C-terminal domain or this domain and the partial or total He2 Helicase domain, which would compromise the functionality of LGP2. In conclusion, this is the first study that elucidate the large genomic organization and complex transcriptional regulation of human LGP2, its pattern of sequence generation, and a mode of evolutionary inheritance across species.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"11-20"},"PeriodicalIF":3.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590571","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

4-Phenylbutyric acid mitigates ER stress-induced neurodegeneration in the spinal cords of a GM2 gangliosidosis mouse model. 4-苯基丁酸可减轻GM2神经节苷脂病小鼠模型脊髓中ER应激诱导的神经退行性变。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-01-23 DOI: 10.1093/hmg/ddae153

Fiona E Weaver, Elizabeth White, Allyson M Peek, Colin A Nurse, Richard C Austin, Suleiman A Igdoura

{"title":"4-Phenylbutyric acid mitigates ER stress-induced neurodegeneration in the spinal cords of a GM2 gangliosidosis mouse model.","authors":"Fiona E Weaver, Elizabeth White, Allyson M Peek, Colin A Nurse, Richard C Austin, Suleiman A Igdoura","doi":"10.1093/hmg/ddae153","DOIUrl":"10.1093/hmg/ddae153","url":null,"abstract":"Sandhoff disease (SD), a fatal and rare lysosomal storage disorder (LSD), is caused by a deficiency of the enzyme β-hexosaminidase B and leads to severe accumulation of GM2 gangliosides in lysosomes, primarily within the central nervous system (CNS). This accumulation results in severe neurological impairment, lower motor neuron disease, and death. Currently, there are no effective therapies available for SD. Here, we explored the role of endoplasmic reticulum (ER) stress in the spinal cord during disease progression in an established mouse model of SD and revealed the beneficial outcome of off-label treatment with the FDA-approved drug, 4-phenylbutyric acid (4-PBA). We analyzed the expression and localization of ER stress and cellular apoptosis markers, which revealed significant upregulation of these factors within motor neurons. Additionally, we observed a > 50% reduction in neuronal numbers throughout all spinal cord regions. Our studies also tested the impact of the chemical chaperone 4-PBA on ER stress in mice, and following administration, we observed significant improvements in motor neuromuscular function and life span throughout disease progression. 4-PBA treatment significantly reduced apoptosis in spinal cord neurons and increased the number of choline acetyltransferase (ChAT)-positive neurons, with little effect on astrogliosis or sensory interneurons. Overall, this study provides strong evidence for the role of chronic ER stress in the pathophysiology of SD and highlights 4-PBA as a promising therapeutic treatment for SD and potentially other related LSDs.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"32-46"},"PeriodicalIF":3.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619276","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

Loss of paired immunoglobin-like type 2 receptor B gene associated with age-related macular degeneration impairs photoreceptor function in mouse retina. 与老年性黄斑变性相关的成对免疫球蛋白样 2 型受体 B 基因缺失会损害小鼠视网膜的感光器功能。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-01-23 DOI: 10.1093/hmg/ddae161

Partha Narayan Dey, Nivedita Singh, Lina Zelinger, Zachary Batz, Jacob Nellissery, Noor D White Carreiro, Haohua Qian, Tiansen Li, Robert N Fariss, Lijin Dong, Anand Swaroop

{"title":"Loss of paired immunoglobin-like type 2 receptor B gene associated with age-related macular degeneration impairs photoreceptor function in mouse retina.","authors":"Partha Narayan Dey, Nivedita Singh, Lina Zelinger, Zachary Batz, Jacob Nellissery, Noor D White Carreiro, Haohua Qian, Tiansen Li, Robert N Fariss, Lijin Dong, Anand Swaroop","doi":"10.1093/hmg/ddae161","DOIUrl":"10.1093/hmg/ddae161","url":null,"abstract":"Genome-wide association studies have uncovered mostly non-coding variants at over 60 genetic loci linked to susceptibility for age-related macular degeneration (AMD). To ascertain the causal gene at the PILRB/PILRA locus, we used a CRISPR strategy to produce germline deletions in the mouse paired immunoglobin-like type 2 receptor (Pilr) genes that encode highly related activating (PILRB) and inhibitory (PILRA) receptors. We show that a combined loss of Pilrb1 and Pilrb2, but not Pilra, leads to an early but relatively stationary defect as the electroretinography (ERG) amplitudes of Pilrb1/2-/- mice exhibit a marked reduction as early as postnatal day 15 and do not show additional significant decrease at 3 and 12-months. No alterations are evident in Müller glia, microglia, bipolar, amacrine and horizontal cells based on immunohistochemistry using cell-type specific markers. PILRB immunostaining is specifically detected at the proximal part of photoreceptor outer segment. Reduced expression of select calcium-regulated phototransduction and synapse-associated proteins, including GCAP1 and 2, PDE6b, AIPL1, PSD95, and CTBP1 indicates dysregulation of calcium homeostasis as a possible mechanism of retinal phenotype in Pilrb1/2-/- mice. Our studies suggest a novel function of PILRB in retinal photoreceptors and an association of PILRB, but not PILRA, with AMD pathogenesis.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"64-76"},"PeriodicalIF":3.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619292","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

Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth syndrome. TAFAZZIN缺乏症的干细胞模型揭示了巴特综合征的新型组织特异性病理变化。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-01-23 DOI: 10.1093/hmg/ddae152

Olivia Sniezek Carney, Kodi W Harris, Yvonne Wohlfarter, Kyuna Lee, Grant Butschek, Arianna F Anzmann, Anne Hamacher-Brady, Markus A Keller, Hilary J Vernon

{"title":"Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth syndrome.","authors":"Olivia Sniezek Carney, Kodi W Harris, Yvonne Wohlfarter, Kyuna Lee, Grant Butschek, Arianna F Anzmann, Anne Hamacher-Brady, Markus A Keller, Hilary J Vernon","doi":"10.1093/hmg/ddae152","DOIUrl":"10.1093/hmg/ddae152","url":null,"abstract":"Barth syndrome (BTHS) is a rare mitochondrial disease caused by pathogenic variants in the gene TAFAZZIN, which leads to abnormal cardiolipin (CL) metabolism on the inner mitochondrial membrane. Although TAFAZZIN is ubiquitously expressed, BTHS involves a complex combination of tissue specific phenotypes including cardiomyopathy, neutropenia, skeletal myopathy, and growth delays, with a relatively minimal neurological burden. To understand both the developmental and functional effects of TAZ-deficiency in different tissues, we generated isogenic TAZ knockout (TAZ-KO) and WT cardiomyocytes (CMs) and neural progenitor cells (NPCs) from CRISPR-edited induced pluripotent stem cells (iPSCs). In TAZ-KO CMs we discovered evidence of dysregulated mitophagy including dysmorphic mitochondria and mitochondrial cristae, differential expression of key autophagy-associated genes, and an inability of TAZ-deficient CMs to properly initiate stress-induced mitophagy. In TAZ-deficient NPCs we identified novel phenotypes including a reduction in CIV abundance and CIV activity in the CIII2&CIV2 intermediate complex. Interestingly, while CL acyl chain manipulation was unable to alter mitophagy defects in TAZ-KO CMs, we found that linoleic acid or oleic acid supplementation was able to partially restore CIV abundance in TAZ-deficient NPCs. Taken together, our results have implications for understanding the tissue-specific pathology of BTHS and potential for tissue-specific therapeutic targeting. Moreover, our results highlight an emerging role for mitophagy in the cardiac pathophysiology of BTHS and reveal a potential neuron-specific bioenergetic phenotype.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"101-115"},"PeriodicalIF":3.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619294","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

SMN depletion impairs skeletal muscle formation and maturation in a mouse model of SMA. 在一种 SMA 小鼠模型中，SMN 的缺失会损害骨骼肌的形成和成熟。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-01-23 DOI: 10.1093/hmg/ddae162

Hong Liu, Lucia Chehade, Marc-Olivier Deguise, Yves De Repentigny, Rashmi Kothary

{"title":"SMN depletion impairs skeletal muscle formation and maturation in a mouse model of SMA.","authors":"Hong Liu, Lucia Chehade, Marc-Olivier Deguise, Yves De Repentigny, Rashmi Kothary","doi":"10.1093/hmg/ddae162","DOIUrl":"10.1093/hmg/ddae162","url":null,"abstract":"Spinal muscular atrophy (SMA) is characterized by low levels of the ubiquitously expressed Survival Motor Neuron (SMN) protein, leading to progressive muscle weakness and atrophy. Skeletal muscle satellite cells play a crucial role in muscle fiber maintenance, repair, and remodelling. While the effects of SMN depletion in muscle are well documented, its precise role in satellite cell function remains largely unclear. Using the Smn2B/- mouse model, we investigated SMN-depleted satellite cell biology through single fiber culture studies. Myofibers from Smn2B/- mice were smaller in size, shorter in length, had reduced myonuclear domain size, and reduced sub-synaptic myonuclear clusters-all suggesting impaired muscle function and integrity. These changes were accompanied by a reduction in the number of myonuclei in myofibers from Smn2B/- mice across all disease stages examined. Although the number of satellite cells in myofibers was significantly reduced, those remaining retained their capacity for myogenic activation and proliferation. These findings support the idea that a dysregulated myogenic process could be occurring as early in muscle stem cells during muscle formation and maturation in SMA. Targeting those pathways could offer additional options for combinatorial therapies for SMA.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"21-31"},"PeriodicalIF":3.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590578","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