Disease Models & Mechanisms最新文献_第6页

A hypomorphic model of CPS1 deficiency for investigating the effects of hyperammonemia on the developing nervous system. 磷酸氨甲酰合成酶1 Asn674Ile突变促进酶改变和小鼠高氨血症。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-06-20 DOI: 10.1242/dmm.052303

Stuti Bakshi, Taryn Diep, Brandon J Willis, Rachel Reyes, Grace F Wu, Georgios Makris, Martin Poms, Isabel Day, Qin Sun, Irina Zhuravka, Lindsay Lueptow, Michelle Tang, Gareth A Cromie, Aimée M Dudley, Johannes Häberle, Gerald S Lipshutz

{"title":"A hypomorphic model of CPS1 deficiency for investigating the effects of hyperammonemia on the developing nervous system.","authors":"Stuti Bakshi, Taryn Diep, Brandon J Willis, Rachel Reyes, Grace F Wu, Georgios Makris, Martin Poms, Isabel Day, Qin Sun, Irina Zhuravka, Lindsay Lueptow, Michelle Tang, Gareth A Cromie, Aimée M Dudley, Johannes Häberle, Gerald S Lipshutz","doi":"10.1242/dmm.052303","DOIUrl":"10.1242/dmm.052303","url":null,"abstract":"Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a rare metabolic disorder that, in neonatal onset, is typically characterized by severe life-threatening and neurologically injuring hyperammonemic episodes with high unmet patient need. Patients that retain limited enzyme activity may present later in life with less severe hyperammonemia. CPS1 drives the first step in the urea cycle, the pathway terrestrial mammals utilize to metabolize nitrogen. In order to probe the effect of hyperammonemia on the developing nervous system and explore new therapies, a murine Cps1 exon 3-4 mutant was previously generated. However, these mice die within 24 h of birth, limiting study capabilities. Herein, we developed a novel Cps1 hypomorphic murine model with residual enzyme activity that maintains survival, but with dysfunction of Cps1 that could be detected biochemically. Characterization, based on the orthologous human variant Asn674Ile, revealed that the variant is reproducible, 100% penetrant and biochemically phenocopies the human disorder. The hypomorph presents with elevated ammonia and glutamate, and reduced citrulline, and with an impaired rate of ureagenesis, providing a novel platform to study and develop therapies for CPS1 deficiency.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149565","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

Disruption of Morrbid alleviates autoinflammatory osteomyelitis in Pstpip2-deficient mice. 破坏morbid可减轻pstpip2缺陷小鼠的自身炎症性骨髓炎。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-07-07 DOI: 10.1242/dmm.052176

Qingran Huo, Jiayu Ding, Hongxi Zhou, Yue Wang, Shanshan Wang, Hang He, Lorie Chen Cai, Jingjing Liu, Ge Dong, Zhigang Cai

{"title":"Disruption of Morrbid alleviates autoinflammatory osteomyelitis in Pstpip2-deficient mice.","authors":"Qingran Huo, Jiayu Ding, Hongxi Zhou, Yue Wang, Shanshan Wang, Hang He, Lorie Chen Cai, Jingjing Liu, Ge Dong, Zhigang Cai","doi":"10.1242/dmm.052176","DOIUrl":"10.1242/dmm.052176","url":null,"abstract":"Autoinflammatory diseases (AIDs) are defined as abnormal activation of the innate immune system leading to spontaneous and uncontrolled inflammation. AIDs may affect bone tissue and lead to chronic recurrent multifocal osteomyelitis (CRMO). However, the etiology and treatment of CRMO remain elusive. In previous studies, we reported that loss of Morrbid prevents myeloid-lineage leukemogenesis. Here, we observed that Morrbid and Pstpip2 are co-expressed in mature myeloid cells and hypothesize a pathogenic role for Morrbid in osteomyelitis. We generated a Pstpip2-/- strain with a 5-bp deletion in Pstpip2, and the strain manifests CRMO-like phenotypes. Loss of Morrbid in Pstpip2-/- mice significantly inhibited the initiation and progression of CRMO symptoms and mitigated activation of myeloid cells and the excessive release of inflammatory cytokines. In addition, single-cell transcriptome analysis demonstrated reduction of osteoclasts and inflammatory cells caused by loss of Morrbid in the Pstpip2-/-Morrbid-/- compound mutants. Using murine models, this study profiles the pathological cell landscape of CRMO by single-cell analysis and suggests that reducing the lifespan of inflammatory myeloid cells by targeting Morrbid can be an effective therapy for chronic osteomyelitis.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274347","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

Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders. 区分果蝇轻度、重度和非典型过氧化物酶体生物发生障碍的PEX2和PEX16基因变异严重程度。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-07-28 DOI: 10.1242/dmm.052258

Vanessa A Gomez, Oguz Kanca, Sharayu V Jangam, Saurabh Srivastav, Jonathan C Andrews, Michael F Wangler

{"title":"Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders.","authors":"Vanessa A Gomez, Oguz Kanca, Sharayu V Jangam, Saurabh Srivastav, Jonathan C Andrews, Michael F Wangler","doi":"10.1242/dmm.052258","DOIUrl":"10.1242/dmm.052258","url":null,"abstract":"Peroxisomal biogenesis disorders (PBD) are autosomal recessive diseases caused by mutations in specific PEX genes that impair peroxisome formation, leading to multi-systemic failure. Symptoms vary, even in patients with variants in the same PEX gene. Our goal is to select PEX mutations and use Drosophila to model a severity spectrum based on genotype-phenotype correlations. Utilizing KozakGAL4 (KZ) cassettes, we replaced the coding sequence of Pex with a GAL4 driver, ideal for making 'humanized' flies in which human PEX can replace the fly loss. We generated Pex2KZ and Pex16KZ lines and assessed them in various behavior assays, confirming their severe phenotypes. We performed rescue with human reference, variant PEX2 and PEX16 alleles, and phenotypic rescue was observed when human PEX2Ref or PEX16Ref were expressed in Pex2KZ or Pex16KZ flies, respectively. We identified a severity spectrum for PEX2 and PEX16 alleles, with some missense mutations exhibiting severity comparable to truncations. Alleles linked to mild PBD showed partial rescue, while variants associated with atypical ataxia could fully rescue. Drosophila humanization is an effective method to study the range of severity of PBD.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575031","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

Dhdds T206A and Dhdds K42E knock-in mouse models of retinitis pigmentosa 59 are phenotypically similar. Dhdds T206A和Dhdds K42E敲入59型视网膜色素变性小鼠模型在表型上相似。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-08-01 DOI: 10.1242/dmm.052243

Mai N Nguyen, Dibyendu Chakraborty, Jeffrey Messinger, Timothy W Kraft, David M Sherry, Steven J Fliesler, Steven J Pittler

{"title":"Dhdds T206A and Dhdds K42E knock-in mouse models of retinitis pigmentosa 59 are phenotypically similar.","authors":"Mai N Nguyen, Dibyendu Chakraborty, Jeffrey Messinger, Timothy W Kraft, David M Sherry, Steven J Fliesler, Steven J Pittler","doi":"10.1242/dmm.052243","DOIUrl":"10.1242/dmm.052243","url":null,"abstract":"Dehydrodolichyl diphosphate synthase complex subunit (DHDDS) is required for protein glycosylation in eukaryotes, and variants. Surprisingly, three variant alleles (K42E/K42E, T206A/K42E and R98W/K42E) have been reported to cause retinitis pigmentosa 59 (RP59). Because T206A only has been reported to occur heterozygously with K42E, we generated homozygous and hererozygous mutants - i.e. T206A/T206A and T206A/K42E, respectively - in mice to assess the effect of the T206A allele. By postnatal age of 12 month (PN 12-mo), T206A/T206A and T206A/K42E mice exhibited reduction of inner nuclear layer thickness as observed in K42E/K42E mice. Electroretinography (ERG) revealed a reduction in b-waves, but spared reduction in a-wave amplitudes. By PN 3-mo, ERG c- and d-waves were significantly attenuated in all phenotypes. Consistent with a reduction in inner nuclear layer thickness as seen by using optical coherence tomography (OCT), cell loss observed by histology, as well as bipolar and amacrine cell densities were reduced in all Dhdds mutant phenotypes compared to those of PN 8-12 mo age-matched controls. These results indicated that the DHDDS T206A allele, like the K42E allele, causes retinal disease, probably through a common pathobiological mechanism. We propose that the physiological basis of retinal dysfunction in RP59 involves defective photoreceptor to bipolar cell synaptic transmission with concomitant bipolar/amacrine cell degeneration.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505088","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

Long-term, age-associated activity quantification in the DE50-MD dog model of Duchenne muscular dystrophy. 杜氏肌营养不良（DMD） DE50-MD犬模型的长期、年龄相关活动量化。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-07-14 DOI: 10.1242/dmm.052135

Kamila Karimjee, Rachel C M River, Emil Olsen, Yu-Mei Chang, Dominic J Wells, Monica A Daley, Richard J Piercy

{"title":"Long-term, age-associated activity quantification in the DE50-MD dog model of Duchenne muscular dystrophy.","authors":"Kamila Karimjee, Rachel C M River, Emil Olsen, Yu-Mei Chang, Dominic J Wells, Monica A Daley, Richard J Piercy","doi":"10.1242/dmm.052135","DOIUrl":"10.1242/dmm.052135","url":null,"abstract":"Animal models with a clinically relevant phenotype remain important for robust evaluation of novel therapeutics for the fatal X-linked genetic disorder Duchenne muscular dystrophy (DMD). Demonstration of functional improvement is crucial for both patients and regulatory authorities. Here, we investigate non-invasive methods to quantify activity changes in DE50-MD dogs. Using collar-based Axivity-AX3 tri-axial accelerometers, we measured activity in affected DE50-MD male dogs (3-8 per age point) and littermate wild-type (WT) male controls (3-13 per age point) at monthly intervals from 3 to 18 months of age. Acceleration vector magnitudes were used to derive a series of activity measures over 24 h. Mixed model analyses were used to examine differences between affected and WT groups at different ages. Activity indicators for DE50-MD dogs were significantly higher for percent time spent at rest (P<0.001) and significantly lower for all other activity indicators (all P<0.05), when compared to age-matched WT dogs. Relatively few animals would be required to detect treatment effects with adequate power using these unbiassed, selected and composite activity measures. Our approach reveals opportunities for cross-model standardisation of activity monitoring.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215186","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

An in vitro model of the epithelial airway reveals a key function for EHF in lung homeostasis and disease. 体外上皮气道模型揭示了EHF在肺稳态和疾病中的关键功能。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-07-01 DOI: 10.1242/dmm.052106

Laetitia Pinte, Marta Vila-Gonzalez, Eleanor C Williams, Erika Causa, Ricardo Fradique, Tekle Pauzaite, Charlotte Passemar, Silvia Becca, Christopher Gribben, Shiqi Ye, Maha Al-Thani, Fabian Bachinger, Floris J M Roos, James A Nathan, Irina Mohorianu, Andres Floto, Pietro Cicuta, Ludovic Vallier

{"title":"An in vitro model of the epithelial airway reveals a key function for EHF in lung homeostasis and disease.","authors":"Laetitia Pinte, Marta Vila-Gonzalez, Eleanor C Williams, Erika Causa, Ricardo Fradique, Tekle Pauzaite, Charlotte Passemar, Silvia Becca, Christopher Gribben, Shiqi Ye, Maha Al-Thani, Fabian Bachinger, Floris J M Roos, James A Nathan, Irina Mohorianu, Andres Floto, Pietro Cicuta, Ludovic Vallier","doi":"10.1242/dmm.052106","DOIUrl":"10.1242/dmm.052106","url":null,"abstract":"In the lung airways, multiple cell types facilitate airflow to alveoli, clearing out debris, particles and pathogens. These vital processes are impeded in chronic inflammatory respiratory diseases, in which the epithelium typically suffers from inflammation, infections and hypoxia. An increasing body of evidence highlights the critical role of modifier genes in responses and resistance against these pathogenic processes. Here, we sought to study the transcription factor EHF, suggested by previous studies as a putative modifier gene, yet its functional role remains ambiguous. To explore this question, we knocked out EHF in human induced pluripotent stem cell-derived lung cells and examined the subsequent phenotypic and functional impacts. Loss of EHF enhanced cystic fibrosis transmembrane conductance regulator activity, led to transcriptomic changes in basal cells, increased transepithelial electrical resistance and reduced HIF-1α-mediated response to hypoxia. Here, we show that variation in EHF expression can impact lung diseases through several mechanisms, thereby highlighting prospects for novel therapies.","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/PMC12264733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539423","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

Label-free morphology-based phenotypic analysis of spinal and bulbar muscular atrophy muscle cell models. 脊髓和球性肌萎缩细胞模型的无标记形态学表型分析。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-25 DOI: 10.1242/dmm.052220

Kenji Sakakibara, Kenjiro Tanaka, Madoka Iida, Yuta Imai, Mai Okada, Kentaro Sahashi, Tomoki Hirunagi, Kentaro Maeda, Ryuji Kato, Masahisa Katsuno

{"title":"Label-free morphology-based phenotypic analysis of spinal and bulbar muscular atrophy muscle cell models.","authors":"Kenji Sakakibara, Kenjiro Tanaka, Madoka Iida, Yuta Imai, Mai Okada, Kentaro Sahashi, Tomoki Hirunagi, Kentaro Maeda, Ryuji Kato, Masahisa Katsuno","doi":"10.1242/dmm.052220","DOIUrl":"10.1242/dmm.052220","url":null,"abstract":"Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by CAG trinucleotide expansion in the androgen receptor (AR) gene. To improve the quality of in vitro cell-based assays for the evaluation of potential drug candidates for SBMA, we developed a morphology-based phenotypic analysis for a muscle cell model of SBMA that involves multiparametric morphological profiling to quantitatively assess the therapeutic effects of drugs on muscle cell phenotype. The analysis was validated using dihydrotestosterone and pioglitazone, which have been shown to exacerbate and ameliorate the pathophysiology of SBMA, respectively. Gene expression analysis revealed activation of the JNK pathway in the SBMA cells compared to the control cells. Phenotypic analysis revealed the effect of naratriptan, a JNK inhibitor, on the phenotypic changes of SBMA cells, and the results were confirmed by LDH assays. We then trained a predictive machine learning model to classify the drug responses, and it successfully discriminated between pioglitazone-type and naratriptan-type morphological profiles based on their morphological characteristics. Our morphology-based phenotypic analysis provides a noninvasive and efficient screening method to accelerate the development of therapeutics for SBMA.","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/PMC12233066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233500","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

P23H rhodopsin accumulation causes transient disruptions to synaptic protein levels in rod photoreceptors in a model of retinitis pigmentosa. P23H视紫红质积累导致杆状光感受器突触蛋白水平的短暂中断。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-23 DOI: 10.1242/dmm.052256

Samantha L Thompson, Sophie M Crowder, Maryam Hekmatara, Emily R Sechrest, Wen-Tao Deng, Michael A Robichaux

{"title":"P23H rhodopsin accumulation causes transient disruptions to synaptic protein levels in rod photoreceptors in a model of retinitis pigmentosa.","authors":"Samantha L Thompson, Sophie M Crowder, Maryam Hekmatara, Emily R Sechrest, Wen-Tao Deng, Michael A Robichaux","doi":"10.1242/dmm.052256","DOIUrl":"10.1242/dmm.052256","url":null,"abstract":"Rod photoreceptor neurons in the retina detect scotopic light through the visual pigment rhodopsin (Rho) in their outer segment (OS). Efficient Rho trafficking to the OS through the inner rod compartments is critical for long-term rod health. However, given the importance of protein trafficking to the OS, little is known about the trafficking of rod synaptic proteins. Furthermore, the subcellular impact of Rho mislocalization on rod synapses (i.e. 'spherules') has not been investigated. In this study, we used super-resolution and electron microscopies, along with proteomics, to perform a subcellular analysis of Rho synaptic mislocalization in P23H-Rho-RFP mutant mice. We discovered that mutant P23H-Rho-RFP protein mislocalized in distinct accumulations within the spherule cytoplasm, which we confirmed with adeno-associated virus overexpression. Additionally, we found specific synaptic protein abundance differences in P23H-Rho-RFP mice. Interestingly, in P23H knock-in mice with no RFP tag, we detected no synaptic protein abundance changes. In rd10 mutant rods, Rho mislocalized along the spherule plasma membrane, and there were synaptic protein abundance differences at postnatal day 20. Our findings demonstrate that some rod photoreceptor synaptic proteins are sensitive to Rho mislocalization.","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/PMC12233068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215187","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

DWORF expression is reduced in a large animal model of Duchenne muscular dystrophy. DWORF在大型杜氏肌营养不良动物模型中表达降低。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-25 DOI: 10.1242/dmm.052285

Aaron M Gibson, Xiufang Pan, Omar Brito-Estrada, James A Teixeira, Lauren K Carl, Yongping Yue, Michael L Kamradt, Matthew J Burke, Caris A Wadding-Lee, Gang Yao, Roland W Herzog, Dongsheng Duan, Catherine A Makarewich

{"title":"DWORF expression is reduced in a large animal model of Duchenne muscular dystrophy.","authors":"Aaron M Gibson, Xiufang Pan, Omar Brito-Estrada, James A Teixeira, Lauren K Carl, Yongping Yue, Michael L Kamradt, Matthew J Burke, Caris A Wadding-Lee, Gang Yao, Roland W Herzog, Dongsheng Duan, Catherine A Makarewich","doi":"10.1242/dmm.052285","DOIUrl":"10.1242/dmm.052285","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease driven by cytosolic calcium overload, which leads to muscle degeneration. Sarco/endoplasmic reticulum calcium ATPase (SERCA), a key regulator of cytosolic calcium levels, exhibits reduced activity in animal models of DMD and human patients. Dwarf open reading frame (DWORF), a positive SERCA regulator, is downregulated in mdx DMD mice, and adeno-associated virus-mediated DWORF overexpression has been shown to ameliorate DMD cardiomyopathy. The canine DMD model provides a crucial bridge for translating findings from mice to humans. To investigate DWORF expression in this model, we developed a canine-specific anti-DWORF antibody, as the existing murine antibody is ineffective. This antibody detected DWORF in human, pig, cat and rabbit muscle, but not in mouse muscle. DWORF was absent in muscle tissues of neonatal normal dogs but highly expressed in those of adult dogs. In DMD-affected dogs aged 8 months or older, DWORF expression was significantly reduced in both cardiac and skeletal muscle. This study establishes a foundation for evaluating DWORF-based gene therapy in the canine DMD model, advancing the potential for clinical translation.","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/PMC12233064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483552","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

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