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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
Priyanka Mungara, Kristina MacNaughton, A K M Shahid Ullah, Grace Essuman, Forough Chelangarimiyandoab, Rizwan Mumtaz, J Christopher Hennings, Christian A Hübner, Dominique Eladari, R Todd Alexander, Emmanuelle Cordat
{"title":"Urinary sodium wasting and disrupted collecting duct function in mice with distal renal tubular acidosis mutations.","authors":"Priyanka Mungara, Kristina MacNaughton, A K M Shahid Ullah, Grace Essuman, Forough Chelangarimiyandoab, Rizwan Mumtaz, J Christopher Hennings, Christian A Hübner, Dominique Eladari, R Todd Alexander, Emmanuelle Cordat","doi":"10.1242/dmm.052138","DOIUrl":"10.1242/dmm.052138","url":null,"abstract":"<p><p>Distal renal tubular acidosis (dRTA) results in metabolic acidosis owing to impaired urinary acidification and can result in an unexplained urinary sodium-wasting phenotype. We report the generation and characterization of a novel dRTA mutant mouse line, Ae1 L919X knock-in (KI). Homozygous L919X KI mice exhibit typical dRTA features, including reduced ability to acidify urine in response to an acid load. This renal acidification defect was associated with a reduced number of kAE1-positive type A intercalated cells. To assess whether these mice exhibit urinary sodium wasting, homozygous L919X KI mice and the previously described R607H KI mice were fed a salt-depleted acid diet. In line with human patients, both mouse strains exhibited urinary sodium loss. Additionally, we identified increased expression of tight junction proteins claudin 4 and claudin 10b, suggesting a compensatory paracellular pathway. Consistent with data from human patients, L919X KI mice displayed a milder phenotype than that of R607H KI mice. Our findings reveal that both mouse strains are appropriate models for dRTA with a urinary salt-wasting phenotype and compensatory upregulation of the paracellular pathway.</p>","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/PMC12128221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971036","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}
Samia L Pratt, Mariana Zarate-Mendez, Lidiia Koludarova, Sonja Jansson, Mikko Airavaara, Irena Hlushchuk, David Coleman, Caleb Heffner, Rita Horvath, Brendan J Battersby, Robert W Burgess
{"title":"Evaluating the feasibility of gene replacement strategies to treat MTRFR deficiency.","authors":"Samia L Pratt, Mariana Zarate-Mendez, Lidiia Koludarova, Sonja Jansson, Mikko Airavaara, Irena Hlushchuk, David Coleman, Caleb Heffner, Rita Horvath, Brendan J Battersby, Robert W Burgess","doi":"10.1242/dmm.052120","DOIUrl":"10.1242/dmm.052120","url":null,"abstract":"<p><p>Mitochondrial translation release factor in rescue (MTRFR) catalyzes a termination step in protein synthesis, facilitating release of the nascent chain from mitoribosomes. Pathogenic variants in MTRFR cause MTRFR deficiency and are loss-of-function variants. Here, we tested gene replacement as a possible therapeutic strategy. A truncating mutation (K155*) was generated in mice; however, homozygotes die embryonically whereas mice heterozygous for this K155* allele are normal. We also generated transgenic strains expressing either wild-type human MTRFR or a partially functional MTRFR. Despite dose-dependent phenotypes from overexpression in vitro, neither transgene caused adverse effects in vivo. In K155* homozygous mice, the wild-type MTRFR transgene completely rescued the phenotype with only one copy present, whereas the mutant transgene rescued less efficiently. Detailed evaluation of mice rescued with the wild-type MTRFR transgene revealed no abnormalities. In human induced pluripotent stem cell (hiPSC)-derived knockdown neurons, mitochondrial phenotypes were corrected by AAV9-mediated delivery of MTRFR. Thus, we find no toxicity from truncated gene products or overexpression of MTRFR in vivo, and expression of MTRFR corrects phenotypes in both mouse and hiPSC models.</p>","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/PMC12171093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198479","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}
{"title":"DMM Outstanding Paper Prize 2024 winners: Destynie Medeiros, Karen Ayala Baylon, Hailey Egido-Betancourt, Christopher Chapleau and Wei Li, and Jasmin Scheurer and Birgit Sauer.","authors":"Rachel Hackett","doi":"10.1242/dmm.052481","DOIUrl":"https://doi.org/10.1242/dmm.052481","url":null,"abstract":"<p><p>Disease Models & Mechanisms (DMM) is delighted to announce that the winners of the DMM Outstanding Paper Prize 2024 are Destynie Medeiros, Karen Ayala Baylon, Hailey Egido-Betancourt, Christopher Chapleau and Wei Li for their Research Article (titled 'A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviours in female Rett syndrome mice'), and Jasmin Scheurer and Birgit Sauer for their Resources & Methods article (titled 'Histological and functional characterization of 3D human skin models mimicking the inflammatory skin diseases psoriasis and atopic dermatitis'). The two prizes of £1000 are awarded to the first author(s) of the papers that are judged by the journal's Editors to be the most outstanding contribution to the journal that year.</p>","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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198478","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}