Disease Models & Mechanisms最新文献_第8页

Recessive, pathogenic AARS1 variants display variable loss-of-function and dominant-negative effects. 隐性致病性AARS1变异表现出可变的功能丧失和显性负效应。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-27 DOI: 10.1242/dmm.052006

Molly E Kuo, Kira E Jonatzke, Maclaine Parish, Anthony Antonellis

{"title":"Recessive, pathogenic AARS1 variants display variable loss-of-function and dominant-negative effects.","authors":"Molly E Kuo, Kira E Jonatzke, Maclaine Parish, Anthony Antonellis","doi":"10.1242/dmm.052006","DOIUrl":"10.1242/dmm.052006","url":null,"abstract":"Alanyl-tRNA synthetase 1 (AARS1) has been implicated in multi-system recessive phenotypes and in later-onset dominant neuropathy; to date, no single variant has been associated with both dominant and recessive diseases, raising questions about shared mechanisms between the two inheritance patterns. AARS1 variants associated with recessive disease result in loss-of-function or hypomorphic alleles, and this has been demonstrated, in part, via yeast complementation assays. However, pathogenic alleles have not been assessed in a side-by-side study. Here, we employed a humanized yeast model to evaluate the functional consequences of all AARS1 missense variants reported in recessive disease. The majority of variants showed variable loss-of-function effects, ranging from no growth to significantly reduced growth. These data deem yeast a reliable model to test the effects of AARS1 variants; however, our data also indicate that this model is prone to false-negative results and is not informative for genotype-phenotype studies. We next tested missense variants associated with no growth for dominant-negative effects. Interestingly, K81T and E99G AARS1 demonstrated both loss-of-function and dominant-negative effects, indicating that certain AARS1 variants can cause both dominant and recessive disease phenotypes.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12233060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","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 effects of developmental cadmium exposure on health and disease. 发育期镉暴露对健康和疾病的影响。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-09 DOI: 10.1242/dmm.052038

Kathleen M Hudson, Logan Dameris, Rebecca Lichtler, Michael Cowley

{"title":"The effects of developmental cadmium exposure on health and disease.","authors":"Kathleen M Hudson, Logan Dameris, Rebecca Lichtler, Michael Cowley","doi":"10.1242/dmm.052038","DOIUrl":"10.1242/dmm.052038","url":null,"abstract":"Cadmium (Cd) is a naturally occurring toxic heavy metal found ubiquitously throughout the environment. Anthropogenic activities since the onset of industrialization have led to widespread environmental contamination that has substantially increased human exposure and associated health risks. As one of the top ten chemicals of major public health concern of the World Health Organization, Cd poses significant risks to human health, particularly when exposure occurs during the critical stages of development. Cd accumulates in the placenta and can be detected in cord blood and fetal and neonatal tissues, so it is crucial to understand the consequences of early-life Cd exposure and the underlying molecular mechanisms. In this Review, we provide an overview of the models currently used to study developmental Cd exposure and integrate the findings from epidemiological, animal and in vitro studies. We explore the impacts and mechanisms of early-life Cd exposure on the placenta, growth and development, and organ systems, identifying common themes across diverse model systems. Finally, we pinpoint knowledge gaps and propose key research priorities that will advance our understanding and inform mitigation strategies for reducing the developmental risks of Cd exposure.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 6","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mutant zebrafish lacking slc25a22a show spontaneous seizures and respond to the anti-seizure medication valproic acid. 缺乏slc25a22a的突变斑马鱼表现出自发性癫痫发作，并对抗癫痫药物丙戊酸有反应。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-20 DOI: 10.1242/dmm.052275

So-Hyun Lee, Ting Liang, Gopalakrishnan Chandrasekaran, Jun Zhang, Seong Soon Kim, Sundareswaran Varier Parvathi, Seok Won Lee, Eun-Seo Cho, Hee-Young Shin, Young-Gyu Yoon, Jihoon Jo, Myung Ae Bae, Seok-Yong Choi, Myeong-Kyu Kim

{"title":"Mutant zebrafish lacking slc25a22a show spontaneous seizures and respond to the anti-seizure medication valproic acid.","authors":"So-Hyun Lee, Ting Liang, Gopalakrishnan Chandrasekaran, Jun Zhang, Seong Soon Kim, Sundareswaran Varier Parvathi, Seok Won Lee, Eun-Seo Cho, Hee-Young Shin, Young-Gyu Yoon, Jihoon Jo, Myung Ae Bae, Seok-Yong Choi, Myeong-Kyu Kim","doi":"10.1242/dmm.052275","DOIUrl":"10.1242/dmm.052275","url":null,"abstract":"Epilepsy is a neurological disorder associated with abnormal neuronal activity in the central nervous system, resulting in recurrent seizures. Various anti-seizure medications (ASMs) are effective against epilepsy. However, approximately one-third of patients still do not respond to currently available ASMs either alone or in combination because the etiology of their epilepsy remains unclear. To create a novel zebrafish epilepsy model, we analyzed the exomes of 400 Korean patients with epilepsy via whole-exome sequencing. We found 39 candidate genes and investigated these genes through in situ hybridization and loss-of-function studies, identifying SLC25A22, encoding a mitochondrial glutamate carrier, as a potential epilepsy gene. Subsequently, we generated zebrafish slc25a22a mutants and observed that they displayed spontaneous seizures, high-voltage deflections in local field potentials, and elevated Ca2+ levels propagating from the forebrain to the spinal cord. Of nine ASMs tested, valproic acid (VPA) was able to suppress spontaneous seizure activities in slc25a22a mutant larvae, highlighting the unique anti-seizure effect of VPA in this model. Our findings provide valuable insights into the pathogenesis of epilepsy and suggest slc25a22a as a potential target for novel ASM development.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 6","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Epigenetic reprogramming induced by key metabolite depletion is an evolutionarily ancient path to tumorigenesis. 由关键代谢物耗竭引起的表观遗传重编程是一种进化上古老的肿瘤发生途径。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-16 DOI: 10.1242/dmm.052313

Zhe Chen, Xiaomeng Zhang, Mingxi Deng, Chongyang Li, Thi Thuy Nguyen, Min Liu, Kun Dou, Toyotaka Ishibashi, Jiguang Wang, Yan Yan

{"title":"Epigenetic reprogramming induced by key metabolite depletion is an evolutionarily ancient path to tumorigenesis.","authors":"Zhe Chen, Xiaomeng Zhang, Mingxi Deng, Chongyang Li, Thi Thuy Nguyen, Min Liu, Kun Dou, Toyotaka Ishibashi, Jiguang Wang, Yan Yan","doi":"10.1242/dmm.052313","DOIUrl":"10.1242/dmm.052313","url":null,"abstract":"Tumor growth is a challenge for multicellular life forms. Contrary to human tumors, which take years to form, tumors in short-living species can arise within days without accumulating multiple mutations, raising the question whether the paths to tumorigenesis in diverse species have any commonalities. In a fly tumor model caused by loss of cell polarity genes, we identified two key metabolic changes: first, systemic depletion of acetyl-CoA leading to a reduction in histone acetylation levels and stochastic silencing of actively transcribed genes; and second, defects in the methionine cycle causing systemic depletion of S-adenosyl methionine, which further reduces histone methylation levels and causes stochastic activation of transposons. Perturbation of the methionine metabolic process inhibits tumor growth. To understand the evolutionary origin of tumorigenesis, we performed comparative studies of fly and human tumors and found that human tumors with metabolic signatures similar to those of fly tumors have a lower mutational load, younger patient age and lower DNA methylation levels. This study indicates that depletion of key metabolites is an evolutionarily ancient driving force for tumorigenesis.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 6","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","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 anti-cancer transition-state inhibitor MTDIA inhibits human MTAP, inducing autophagy in humanized yeast. 抗癌甲基硫代腺苷磷酸化酶过渡态抑制剂诱导人源化酵母自噬。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-30 DOI: 10.1242/dmm.052173

Namal V Coorey, Isaac Tollestrup, Peter W Bircham, Jeffrey P Sheridan, Gary B Evans, Vern L Schramm, Paul H Atkinson, Andrew B Munkacsi

{"title":"The anti-cancer transition-state inhibitor MTDIA inhibits human MTAP, inducing autophagy in humanized yeast.","authors":"Namal V Coorey, Isaac Tollestrup, Peter W Bircham, Jeffrey P Sheridan, Gary B Evans, Vern L Schramm, Paul H Atkinson, Andrew B Munkacsi","doi":"10.1242/dmm.052173","DOIUrl":"10.1242/dmm.052173","url":null,"abstract":"Methylthioadenosine-DADMe immucillin-A (MTDIA) is a transition-state analog that potently inhibits the human protein 5'-methylthioadenosine phosphorylase (MTAP) at picomolar concentrations and elicits anti-tumor activity against lung, prostate, colon, cervical, head and neck, and triple-negative breast cancers in cell and animal models. The anti-cancer mechanisms of MTDIA involve elevated methylthioadenosine levels but are not fully understood. The yeast protein MEU1 is functionally equivalent to human MTAP. To gain further understanding, we performed chemical genetic analyses via gene deletion and GFP-tagged protein libraries in yeast that express a member of the human equilibrative nucleoside transporter (ENT) family to permit MTDIA uptake. Genomic and proteomic analyses identified genes and proteins critical to MTDIA bioactivity. Network analysis of these genes and proteins revealed an important link to ribosomal function, which was confirmed by observing reduced levels of ribosomal subunit proteins. Network analysis also implicated autophagy, which was confirmed by analyzing intracellular trafficking of GFP-Atg8 and Phloxine B viability. In yeast, a comparable effect occurred after deletion of MEU1, indicating a single target for MTDIA in yeast. Overall, our yeast model reveals specific components of the ribosome as well as induction of autophagy as integral mechanisms that mediate the bioactivity of MTDIA.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12231107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of alcohol on the transcriptome, methylome and metabolome of in vitro gastrulating human embryonic cells. 酒精对体外原肠胚人胚胎细胞转录组、甲基组和代谢组的影响

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-18 DOI: 10.1242/dmm.052150

E Wallén, K Rämö, J Vehviläinen, J Sokka, M Lehtonen, T Otonkoski, R Trokovic, P Auvinen, O Kärkkäinen, N Kaminen-Ahola

{"title":"Effects of alcohol on the transcriptome, methylome and metabolome of in vitro gastrulating human embryonic cells.","authors":"E Wallén, K Rämö, J Vehviläinen, J Sokka, M Lehtonen, T Otonkoski, R Trokovic, P Auvinen, O Kärkkäinen, N Kaminen-Ahola","doi":"10.1242/dmm.052150","DOIUrl":"10.1242/dmm.052150","url":null,"abstract":"Prenatal alcohol exposure (PAE) affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neurodevelopmental disorders and birth defects. To explore the effects of PAE on gastrulation, we used an in vitro model with subchronic moderate (20 mM) and severe (70 mM) ethanol exposures during the differentiation of human embryonic stem cells into germ layer cells. We analyzed genome-wide gene expression (mRNA sequencing), DNA methylation (EPIC Illumina microarrays) and metabolome (non-targeted LC-MS) of the endodermal, mesodermal and ectodermal cells. The largest number of ethanol-induced alterations were observed in endodermal cells, whereas the most prominent changes were in ectodermal cells. Methionine metabolism and genes of the main signaling pathways involved in gastrulation and body patterning were affected by ethanol in all germ layers. Many of the altered genes, including BMP4, FGF8, SIX3 and LHX2, have previously been associated with PAE and phenotypes of FASD, like defects in heart and corpus callosum development as well as holoprosencephaly. Our findings support the early origin of alcohol-induced developmental disorders and strengthen the role of methionine cycle in the etiology of FASD.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

frizzled 5 mutant zebrafish are genetically sensitised to developing microphthalmia and coloboma. Frizzled5突变斑马鱼在基因上对小眼症和结肠瘤敏感。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-10 DOI: 10.1242/dmm.052284

Clinton Monfries, Stephen Carter, Paris Ataliotis, Aya Bseisu, Mahum Shaikh, Maria Hernández-Bejarano, Mohammed Fourteia, Mara Ioana Maftei, Rodrigo M Young, Stephen W Wilson, Gaia Gestri, Florencia Cavodeassi

{"title":"frizzled 5 mutant zebrafish are genetically sensitised to developing microphthalmia and coloboma.","authors":"Clinton Monfries, Stephen Carter, Paris Ataliotis, Aya Bseisu, Mahum Shaikh, Maria Hernández-Bejarano, Mohammed Fourteia, Mara Ioana Maftei, Rodrigo M Young, Stephen W Wilson, Gaia Gestri, Florencia Cavodeassi","doi":"10.1242/dmm.052284","DOIUrl":"10.1242/dmm.052284","url":null,"abstract":"Microphthalmia and coloboma are structural malformations of the eyes that arise from defective morphogenesis and are among the most severe defects associated with paediatric blindness. Frizzled class receptor 5 (FZD5) is a Wnt receptor expressed in the developing eye, and individuals with variants in FZD5 exhibit microphthalmia/coloboma, supporting a role for this receptor in human eye formation. Here, we show that zebrafish fzd5 mutants homozygous for complete loss-of-function or predicted dominant-negative alleles display no obvious eye defects during embryogenesis. Rather, they develop eye defects comparable to those described in humans only upon simultaneous abrogation of additional genes associated with ocular malformations. Thus, eye development can occur normally in the absence of Fzd5 in zebrafish, but mutants are sensitised to developing eye malformations. By exploiting the sensitised nature of the fzd5 mutants, we further identified angio-associated migratory cell protein (aamp) as a novel gene involved in eye morphogenesis. Overall, our study confirms the importance of considering multiple genetic contributions when searching for the molecular aetiology of ocular malformations in humans.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","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 conserved epilepsy-associated gene co-expression module identifies increased metabolic rate as a shared pathomechanism. 保守的癫痫相关基因共表达模块确定代谢率增加是一个共同的病理机制。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-05-22 DOI: 10.1242/dmm.052307

Jingyi Long, Spencer G Jones, Ana Serna, Boyd van Reijmersdal, Franziska Kampshoff, Sara Aibar, Patrik Verstreken, Martijn A Huynen, Kevin Lüthy, Mireia Coll-Tané, Annette Schenck

{"title":"A conserved epilepsy-associated gene co-expression module identifies increased metabolic rate as a shared pathomechanism.","authors":"Jingyi Long, Spencer G Jones, Ana Serna, Boyd van Reijmersdal, Franziska Kampshoff, Sara Aibar, Patrik Verstreken, Martijn A Huynen, Kevin Lüthy, Mireia Coll-Tané, Annette Schenck","doi":"10.1242/dmm.052307","DOIUrl":"https://doi.org/10.1242/dmm.052307","url":null,"abstract":"Epilepsy is a mechanistically complex, incompletely understood neurological disorder. To uncover novel converging mechanisms in epilepsy, we used Drosophila whole-brain single-cell RNA sequencing to refine and characterize a previously proposed human epilepsy-associated gene co-expression network (GCN). We identified a conserved co-expressed module of 26 genes, which comprises fly orthologs of 13 epilepsy-associated genes and integrates synaptic and metabolic functions. Over one-third of the Drosophila pan-neuronal knockdown models targeting this module exhibited altered seizure-like behaviors in response to mechanical or heat stress. These knockdown models recapitulated seizures associated with four epilepsy-associated genes, identified two novel epilepsy candidate genes, and three genes of which knockdown conferred seizure protection. Most knockdown models with altered seizure susceptibility showed changes in metabolic rate and levels of phosphorylated adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis. Enhancing AMPK activity increased seizure resistance in a dose-dependent manner. Our findings show that Drosophila single-cell expression data and behavior can aid functional validation of human GCNs and highlight a role for metabolism in modifying seizure susceptibility.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Overgrowth-intellectual disability disorders: progress in biology, patient advocacy and innovative therapies. 过度生长-智力障碍：生物学进展，患者倡导和创新疗法。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-05-01 Epub Date: 2025-05-12 DOI: 10.1242/dmm.052300

Cooper Atterton, Isabella Trew, Jessica M Cale, May T Aung-Htut, Kerry Grens, Jill Kiernan, Christal G Delagrammatikas, Michael Piper

{"title":"Overgrowth-intellectual disability disorders: progress in biology, patient advocacy and innovative therapies.","authors":"Cooper Atterton, Isabella Trew, Jessica M Cale, May T Aung-Htut, Kerry Grens, Jill Kiernan, Christal G Delagrammatikas, Michael Piper","doi":"10.1242/dmm.052300","DOIUrl":"10.1242/dmm.052300","url":null,"abstract":"Overgrowth-intellectual disability (OGID) syndromes encompass a group of rare neurodevelopmental disorders that frequently share common clinical presentations. Although the genetic causes of many OGID syndromes are now known, we lack a clear mechanistic understanding of how such variants disrupt developmental processes and ultimately culminate in overgrowth and neurological symptoms. Patient advocacy groups, such as the Overgrowth Syndromes Alliance (OSA), are mobilising patients, families, clinicians and researchers to work together towards a deeper understanding of the clinical needs of patients with OGID, as well as to understand the fundamental biology of the relevant genes, with the goal of developing treatments. In this Review, we summarise three OGID syndromes encompassed by the OSA, namely Sotos syndrome, Malan syndrome and Tatton-Brown-Rahman syndrome. We discuss similarities and differences in the biology behind each disorder and explore future approaches that could potentially provide a way to ameliorate some of the unmet clinical needs of patients with OGID.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 5","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12091874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","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 murine model of Barth syndrome recapitulates human cardiac and skeletal muscle phenotypes. 他法嗪致心肌和骨骼肌选择性失活的Barth综合征小鼠模型。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-05-01 Epub Date: 2025-05-19 DOI: 10.1242/dmm.052077

Erika Yazawa, Erin M Keating, Suya Wang, Mason E Sweat, Qing Ma, Yang Xu, Michael Schlame, William T Pu

{"title":"A murine model of Barth syndrome recapitulates human cardiac and skeletal muscle phenotypes.","authors":"Erika Yazawa, Erin M Keating, Suya Wang, Mason E Sweat, Qing Ma, Yang Xu, Michael Schlame, William T Pu","doi":"10.1242/dmm.052077","DOIUrl":"10.1242/dmm.052077","url":null,"abstract":"Barth syndrome is a mitochondrial disorder with hallmarks of cardiac and skeletal muscle weakness. It is caused by pathogenic variants in the X-linked gene tafazzin (TAZ), required for cardiolipin remodeling. Previously described germline and conditional Taz knockout models are not ideal for therapeutic development because they lack the combination of robust survival to adulthood, cardiomyopathy and skeletal muscle weakness. We characterized a cardiac and skeletal muscle-specific Taz knockout model (TazmKO) in which Cre recombinase is expressed from the muscle creatine kinase promoter (mCK-Cre). TazmKO mice survived normally. Cardiolipin composition was abnormal in both heart and skeletal muscle. TazmKO had reduced heart function by 2 months of age, and function progressively declined thereafter. Reduced treadmill endurance and diminished peak oxygen consumption were evident by 3 months of age, suggesting reduced skeletal muscle function. Electron microscopy showed abnormalities in mitochondrial structure and distribution. Overall, TazmKO mice display diminished cardiac function and exercise capacity while maintaining normal survival. This model will be useful for studying the effects of TAZ deficiency in striated muscles and for testing potential therapies for Barth syndrome.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0