Human molecular genetics最新文献

{"title":"Alpha-synuclein modulates the positioning of endolysosomes in melanoma cells.","authors":"Nirjhar M Aloy, Maria Ericsson, Brandon Hartman, Stephan N Witt","doi":"10.1093/hmg/ddaf096","DOIUrl":"10.1093/hmg/ddaf096","url":null,"abstract":"<p><p>The Parkinson's disease-associated protein, alpha-synuclein (α-syn; SNCA) is suspected of promoting melanoma progression. We recently knocked out SNCA in the human cutaneous melanoma cell line SK-MEL-28 to try to deduce the role of α-syn in melanoma progression. Compared to control cells, the SK-MEL-28 SNCA-knockout (KO) cells have significantly inhibited growth, invasion, and migration, and the levels of the neural adhesion protein L1CAM and the transferrin receptor (TFR1) are significantly reduced. In this study, using transmission electron microscopy and immunofluorescence we show that SK-MEL-28 SNCA-KO cells relative to control cells exhibit an (i) increased density of endolysosomes; (ii) increased perinuclear positioning of large (> 800 nm) endolysosomes; and (iii) decreased levels of the tetraspanins CD9 and CD81. Based on these results, we infer that α-syn disrupts the balance between anterograde and retrograde traffic; thus, we propose that α-syn is an accessory factor that that positively modulates the anterograde transport of endolysosomes and that loss of α-syn expression results events (i)-(iii). We infer that low levels of L1CAM and CD81 (and other membrane proteins) are likely the underlying reason for the significantly reduced invasiveness and migratory properties of SK-MEL-28 SNCA-KO cells.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1433-1445"},"PeriodicalIF":3.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12368772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct single cell-type gene expression analysis in peripheral blood: novel ratio-based gene expression biomarkers using 2 novel monocyte reference genes (PSAP and CTSS) for detection of bacterial infection.","authors":"Nelson L S Tang, Tsz-Ki Kwan, Dan Huang, Suk-Ling Ma, Kwong-Sak Leung","doi":"10.1093/hmg/ddaf103","DOIUrl":"10.1093/hmg/ddaf103","url":null,"abstract":"<p><strong>Background: </strong>To determine single-cell-type gene expression in peripheral blood (PB) requires either prior cell sorting or single-cell RNA sequencing. We developed a novel ratio-based biomarker (RBB) called Direct Leukocyte Subpopulation-Transcript Abundance (DIRECT LS-TA) that allows quantification of monocyte-specific gene expression directly from PB without cell sorting.</p><p><strong>Methods: </strong>DIRECT LS-TA leverages proportional cell counts and differential gene expression profiles among leukocyte subpopulations to identify monocyte-informative genes. Using a new ICEBERG plot (Figure 1) based on a mathematical model of cell-mixture gene expression, we shortlisted genes with 2.5-fold higher expression in isolated monocytes compared to PB, indicating > 50% of transcript contribution by monocytes alone. PSAP and CTSS were identified as monocyte informative reference genes with low biological variation. Using one of them as the denominator, another monocyte informative target gene is used as the numerator to derive the RBB. The method was validated for detection of host response towards bacterial infection across multiple datasets.</p><p><strong>Findings: </strong>Over 50 monocyte-informative genes were identified, including immune response genes such as VNN1, IL1B, NLRC4 and IFI44L. DIRECT LS-TA results showed excellent correlation with gold standard isolated monocyte expression (R2 = 0.55-0.97). VNN1 RBB showed consistent upregulation across five datasets (median 2.7-fold, P < 10-8) with good diagnostic performance (AUC = 0.84-0.99). Other genes including NLRC4, CYP1B1 and NFKBIZ were also useful biomarkers.</p><p><strong>Conclusion: </strong>DIRECT LS-TA provides a reliable way of quantification of monocyte-specific gene expression from PB without the need of cell sorting and demonstrated potential use for rapid infection detection and antibiotic stewardship.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1458-1470"},"PeriodicalIF":3.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12368773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Familial ALS/FTD-associated RNA-binding deficient TDP-43 mutants cause neuronal and synaptic transcript dysregulation in vitro.","authors":"Molly Magarotto, Richard T Gawne, Gabriele Vilkaite, Marcello Beltrami, Andrew S Mason, Han-Jou Chen","doi":"10.1093/hmg/ddaf111","DOIUrl":"10.1093/hmg/ddaf111","url":null,"abstract":"<p><p>TDP-43 is an RNA-binding protein constituting the pathological inclusions observed in ~ 95% of ALS and ~ 50% of FTD patients. In ALS and FTD, TDP-43 mislocalises to the cytoplasm and forms insoluble, hyperphosphorylated and ubiquitinated aggregates that enhance cytotoxicity and contribute to neurodegeneration. Despite its primary role as an RNA/DNA-binding protein, how RNA-binding deficiencies contribute to disease onset and progression are little understood. Among many identified familial mutations in TDP-43 causing ALS/FTD, only two mutations cause an RNA-binding deficiency, K181E and K263E. In this study, we used CRISPR/Cas9 to knock-in the two disease-linked RNA-binding deficient mutations in SH-SY5Y cells, generating both homozygous and heterozygous versions of the mutant TDP-43 to investigate TDP-43-mediated neuronal disruption. Significant changes were identified in the transcriptomic profiles of these cells, in particular, between K181E homozygous and heterozygous cells, with the most affected genes involved in neuronal differentiation and synaptic pathways. This result was validated in cell studies where the neuronal differentiation efficiency and neurite morphology were compromised in TDP-43 cells compared to unmodified control. Interestingly, divergent neuronal regulation was observed in K181E-TDP-43 homozygous and heterozygous cells, suggesting a more complex signalling network associated with TDP-43 genotypes and expression level which warrants further study. Overall, our data using cell models expressing the ALS/FTD disease-causing RNA-binding deficient TDP-43 mutations at endogenous levels show a robust impact on transcriptomic profiles at the whole gene and transcript isoform level that compromise neuronal differentiation and processing, providing further insights on TDP-43-mediated neurodegeneration.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1480-1494"},"PeriodicalIF":3.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527702","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}

{"title":"Novel missense variants in CFL2 affect F-actin depolymerisation and expand the disease spectrum of CFL2-related myopathy.","authors":"Lein N H Dofash, Chiara Folland, Jason Dyke, Emna Farhat, Myriam Chaabouni, Najoua Miladi, Merrilee Needham, Phillipa J Lamont, Catherine Ashton, Gianina Ravenscroft","doi":"10.1093/hmg/ddaf102","DOIUrl":"10.1093/hmg/ddaf102","url":null,"abstract":"<p><p>Cofilin-2, encoded by CFL2, is an actin-binding protein essential for regulating actin filament dynamics in skeletal muscle. Biallelic variants in CFL2 are associated with an ultra-rare, early-onset myopathy typically presenting as nemaline myopathy. Only 10 patients have been described to date from five unrelated families. Here, we describe two new cases from two unrelated families. The first proband presented clinically with rigid spine syndrome and a biopsy keeping with nemaline myopathy. The second proband presented with a relatively mild congenital myopathy which became rapidly progressive in the fourth decade, the muscle biopsy showed cytoplasmic bodies, internal nuclei and ringbinden. Exome and genome sequencing revealed three novel biallelic missense variants in CFL2, a homozygous c.115 T > G; p.(Cys39Gly) in the proband of Family 1, and bi-allelic heterozygous c.256G > A:(p.Asp86Asn), and c.283A > G (p.Lys95Glu) variants in the proband of Family 2. We characterised the effects of these substitutions using an in vitro F-actin depolymerisation assay and showed all three were associated with significantly reduced filamentous actin depolymerisation rates compared to the wildtype. Taken together, our findings are highly suggestive of a CFL2-related disease in these patients. Since CFL2-related myopathies are ultrarare, the application of ACMG/AMP guidelines and the diagnostic reportability of CFL2 variants identified in patients remains a challenge. The actin depolymerisation assay may be useful to elucidate the impact and pathogenicity of additional CFL2 variants and has the potential to guide variant classification in future.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1471-1479"},"PeriodicalIF":3.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12368771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic rerouting of valine and isoleucine oxidation increases survival in zebrafish models of disorders of propionyl-CoA metabolism.","authors":"Sungkook Hong, Joel Pardo, PamelaSara E Head, Katharine T Ellis, Madeline L Arnold, Nathan P Achilly, Blake Carrington, Kevin Bishop, Raman Sood, Lisa Kratz, Jennifer L Sloan, Oleg A Shchelochkov, Charles P Venditti","doi":"10.1093/hmg/ddaf100","DOIUrl":"10.1093/hmg/ddaf100","url":null,"abstract":"<p><p>Branched-chain amino acid (BCAA) oxidation is a multistep process leading to the formation of acetyl-CoA and propionyl-CoA. The syndromes associated with disturbed BCAA oxidation are clinically and biochemically heterogenous. While the common organic acidemias, propionic (PA) and methylmalonic acidemia (MMA), arise from deficient activity of propionyl-CoA carboxylase and methylmalonyl-CoA mutase and are life-threatening conditions with limited treatment options, isobutyryl-CoA dehydrogenase (IBD), and 2-methylbutyryl-CoA dehydrogenase (2-MBD) deficiencies manifest as biochemical traits, with no associated symptoms or consistent metabolic phenotypes. To assess whether the proximal interruption of valine and isoleucine oxidation might represent an approach to treat MMA and PA, we investigated the effects of loss of function of acad8 (encoding IBD) and acadsb (encoding 2-MBD), singly and doubly, on biochemical and morphological findings of zebrafish models of pccb-related propionic acidemia (PA) and mmut methylmalonic acidemia (MMA). Although acad8-/-;acadsb-/- double mutants showed growth failure and early mortality, the proximal interruption of valine and isoleucine oxidation in double (pccb/acad8, pccb/acadsb, mmut/acad8, mmut/acadsb) and triple (pccb/acad8/acadsb, mmut/acad8/acadsb) homozygous mutants improved pccb-/- and mmut-/- survival and reduced propionate-derived toxic metabolites, supporting the rationale for pursuing modulation of IBD and 2-MBD activity as a strategy to reduce the metabolic load and improve clinical outcomes in PA and MMA.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1505-1516"},"PeriodicalIF":3.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The RNA-binding protein DDX39B promotes colorectal adenocarcinoma progression by stabilizing DCLK1.","authors":"Shichao Liu, Shoucai Zhang, Hongxi Zhao, Yingjie Liu, Zeyu Zhang, Xueyan Geng, Maopeng Yin, Yongyuan Liang, Guixi Zheng","doi":"10.1093/hmg/ddaf110","DOIUrl":"10.1093/hmg/ddaf110","url":null,"abstract":"<p><p>DDX39B, a member of the DEAD-box (DDX) RNA helicase family, plays a pivotal role in the post-transcriptional regulation of diverse pathological processes, including tumor progression, viral replication, and neurodegenerative disorders. In this study, we investigated the functional significance of DDX39B in the proliferation and metastasis of colon adenocarcinoma (COAD) and sought to uncover its underlying molecular mechanism. Our findings revealed that DDX39B was markedly upregulated in COAD tumor tissues, and its elevated expression correlated with poor patient prognosis. Functional assays, both in vitro and in vivo, demonstrated that DDX39B substantially enhanced the proliferative and metastatic potential of COAD cells. Mechanistically, DDX39B expression was positively associated with Ki67 levels and was found to facilitate epithelial-mesenchymal transition (EMT) in COAD. As an RNA-binding protein (RBP), DDX39B increased the stability of DCLK1-B mRNA, a variant highly expressed in colorectal cancer known to promote cancer stemness, thereby augmenting its protein expression. Notably, silencing of DCLK1-B effectively abrogated the pro-metastatic effects induced by DDX39B overexpression. Collectively, our results offered novel insights into the oncogenic role of DDX39B and highlighted its potential as a therapeutic target in COAD.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1495-1504"},"PeriodicalIF":3.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527704","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}

{"title":"Second-hit CDH1 gene mechanisms in hereditary diffuse gastric and lobular breast cancer syndrome: frequency and impact on tumorigenesis.","authors":"Giovanni Corso, Francesca Magnoni, Matteo Dal Molin, Elena Marino, Luca Nicosia, Filippo Pesapane, Douglas M Noonan, Adriana Albini","doi":"10.1093/hmg/ddaf092","DOIUrl":"10.1093/hmg/ddaf092","url":null,"abstract":"<p><p>Hereditary diffuse gastric and lobular breast cancer (HDGLBC) is an inherited cancer syndrome predominantly characterized by diffuse gastric cancer (DGC) and lobular breast cancer (LBC). LBC often serves as the initial manifestation of HDGLBC, even in the absence of DGC symptoms. Despite advancements in medical technology and treatment, gastric cancer remains a major health burden globally. Approximately 1%-3% of gastric cancers are attributed to hereditary cancer syndromes, with pathogenic variants in the CDH1 gene being a significant contributor. CDH1 encodes E-cadherin, a protein essential for cell-cell adhesion in epithelial tissues. CDH1 inactivation through germline mutations leads to a high risk of developing DGC and LBC. The inactivation process involves a 'second hit' mechanism, commonly promoter methylation, leading to the loss of E-cadherin expression and subsequent tumorigenesis. Additionally, mechanisms such as loss of heterozygosity and somatic mutations contribute to CDH1 inactivation. Current research highlights the complexity of these mechanisms and their role in HDGLBC pathogenesis. Therapeutic strategies targeting these pathways, including epigenetic drugs and synthetic lethal approaches, show promise in restoring CDH1 function and inhibiting tumor progression. Given the aggressive nature of HDGLBC, early diagnosis and personalized treatment plans are crucial. Surveillance for LBC in CDH1 mutation carriers should be prioritized, considering prophylactic mastectomy and chemoprevention. This narrative review highlights the need for understanding the genetic and epigenetic alterations in HDGLBC, which provide critical insights for developing effective therapies and improving patient outcomes. Further research is necessary to refine these strategies and explore novel therapeutic targets.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1345-1352"},"PeriodicalIF":3.2,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247664","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}

{"title":"KDM2B variants in the CxxC domain impair its DNA-binding ability and cause a distinct neurodevelopmental syndrome.","authors":"Amber S E van Oirsouw, Michael A Hadders, Martijn Koetsier, Edith D J Peters, Nurit Assia Batzir, Tahsin Stefan Barakat, Diana Baralle, Adelyn Beil, Marie-Noëlle Bonnet-Dupeyron, Philip M Boone, Arjan Bouman, Deanna Alexis Carere, Benjamin Cogne, Leslie Dunnington, Laura S Farach, Casie A Genetti, Bertrand Isidor, Louis Januel, Aakash Joshi, Nayana Lahiri, Kristen N Lee, Idit Maya, Meriel McEntagart, Hope Northrup, Mathilde Pujalte, Kate Richardson, Susan Walker, Bobby P C Koeleman, Mariëlle Alders, Richard H van Jaarsveld, Renske Oegema","doi":"10.1093/hmg/ddaf082","DOIUrl":"10.1093/hmg/ddaf082","url":null,"abstract":"<p><p>Rare variants affecting the epigenetic regulator KDM2B cause a recently delineated neurodevelopmental disorder. Interestingly, we previously identified both a general KDM2B-associated episignature and a subsignature specific to variants in the DNA-binding CxxC domain. In light of the existence of a distinct subsignature, we set out to determine if KDM2B CxxC variants are associated with a unique phenotype and disease mechanism. We recruited individuals with heterozygous CxxC variants and assessed the variants' effect on protein expression and DNA-binding ability. We analyzed clinical data from 19 individuals, including ten previously undescribed individuals with seven novel CxxC variants. The core phenotype of the KDM2B-CxxC cohort is more extensive as compared to that of individuals with KDM2B haploinsufficiency. All individuals with CxxC variants presented with developmental delay, mainly in the speech and motor domain, in addition to variable intellectual disability and mild facial dysmorphism. Congenital heart defects were observed in up to 78% of individuals, with additional common findings including musculoskeletal, ophthalmological, and urogenital anomalies, as well as behavioral challenges and feeding difficulties. Functional assays revealed that while mutant KDM2B protein with CxxC variants can be expressed in vitro, its DNA-binding ability is significantly reduced compared to wildtype. This study shows that KDM2B CxxC variants cause a distinct neurodevelopmental syndrome, possibly through a molecular mechanism different from haploinsufficiency.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1353-1367"},"PeriodicalIF":3.2,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De novo missense variants of KCNA3, KCNA4, and KCNA6 cause early onset developmental epileptic encephalopathy.","authors":"Meng-Han Tsai, Chia-Hua Lo, You-Xuan Liu, Sheng-Nan Wu, Cheng-Yen Kuo, Yi-Hsuan Liu, Ying-Chao Chang, Kuan-Lin Lin, Po-Cheng Hung, Hwei-Hsien Chen, Jian-Liang Chen, Chi-Kuang Yao, Eric Hwang, Ya-Jean Wang","doi":"10.1093/hmg/ddaf090","DOIUrl":"10.1093/hmg/ddaf090","url":null,"abstract":"<p><p>Shaker-type potassium channel genes (Kv1) have been linked to human epilepsies, including KCNA1 (Kv1.1), KCNA2 (Kv1.2), and more recently, KCNA3 (Kv1.3) and KCNA6 (Kv1.6). In this study, we report three early-onset epilepsy cases with de novo missense mutations in Shaker-type channel genes, including Kv1.3, KCNA4 (Kv1.4), and Kv1.6, identified through whole exome sequencing trio study. The newly identified Kv1.3-V478M, Kv1.6-T421I, and Kv1.4-V558L mutations are located within the channel selectivity filter or S6 hinge, both critical for channel gating. These variants are in paralogous locations of previously reported pathogenic variant in KCNA2. These mutations do not significantly affect trafficking and plasma membrane localization of the Kv channels. In contrast, our patch-clamp analysis in a cell-based system reveals that all three mutations cause severe loss-of-function channel properties. Additionally, our Drosophila model highlights the detrimental effects of Kv1.3-V478M on neural circuit activity. Current findings suggest that, similar to Kv1.1, Kv1.2, and Kv1.3, both loss-of-function and gain-of-function mutations in Kv1.6 may contribute to the phenotypic variability in epilepsy severity. Our study also extends the list of potassium channel genes implicated in human epilepsy, introducing Kv1.4 as a novel epilepsy-related gene.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1392-1404"},"PeriodicalIF":3.2,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233979","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}

{"title":"Diverse effects of coexpression of human SOD1 variants on motor neuron disease.","authors":"Eiichi Tokuda, Laura Leykam, Per Zetterström, Thomas Brännström, Peter M Andersen, Stefan L Marklund","doi":"10.1093/hmg/ddaf088","DOIUrl":"10.1093/hmg/ddaf088","url":null,"abstract":"<p><p>Mutations in superoxide dismutase-1 (SOD1) are a common cause of amyotrophic lateral sclerosis (ALS). Inheritance is as a rule dominant, but in carriers of the most common mutation, D90A, disease can develop in both homozygous and, more rarely, in heterozygous individuals with unexplained differences in clinical presentation. There is mounting evidence that prion-like spread of SOD1 aggregation is the primary cause of the disease. Two different strains of aggregates have been found to arise in human SOD1 (hSOD1) transgenic mouse models of ALS. Strain A is formed by most mutants including hSOD1G85R and hSOD1WT, whereas hSOD1D90A transgenic mice form a distinct strain B in addition to A. To explore the effects of aggregate strain propensities when hSOD1 variants are coexpressed, we generated digenic hSOD1G85R/WT and hSOD1G85R/D90A mice. Coexpression of hSOD1WT considerably shortened the lifespan of hSOD1G85R mice to the extent expected from the neurotoxicities of the variants alone. In contrast, coexpression of hSOD1D90A had a minimal effect on survival, far smaller than expected. Moreover, time from onset to the end stage was markedly prolonged in the hSOD1G85R/D90A mice. Aggregation of hSOD1 developed concomitantly with motor neuron disease, and the aggregates contained large amounts of both coexpressed variants in both digenic models. Our findings suggest that hSOD1WT has high a capacity to coaggregate with mutants and enhance neurotoxicity. Such interactions may be restricted by differences in strain propensities, which may contribute to the primarily recessive inheritance associated with the hSOD1D90A mutation.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1380-1391"},"PeriodicalIF":3.2,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}