Human molecular genetics最新文献_第3页

Alpha-synuclein modulates the positioning of endolysosomes in melanoma cells. -突触核蛋白调节黑色素瘤细胞内溶酶体的定位。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-16 DOI: 10.1093/hmg/ddaf096

Nirjhar M Aloy, Maria Ericsson, Brandon Hartman, Stephan N Witt

{"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":"https://doi.org/10.1093/hmg/ddaf096","url":null,"abstract":"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.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Calcium homeostasis modulator 2 aggravates α-synuclein-induced neurotoxicity in Parkinson's disease by activating PARP-1 depended Parthanatos. 钙稳态调节剂2通过激活PARP-1依赖性Parthanatos加重α-突触核蛋白诱导的帕金森病神经毒性。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-16 DOI: 10.1093/hmg/ddaf091

Qi Pan, Huanjun Xu, Zongyu Xiao, Guanghao Liu, Huaming Zhang, Yiying Li

{"title":"Calcium homeostasis modulator 2 aggravates α-synuclein-induced neurotoxicity in Parkinson's disease by activating PARP-1 depended Parthanatos.","authors":"Qi Pan, Huanjun Xu, Zongyu Xiao, Guanghao Liu, Huaming Zhang, Yiying Li","doi":"10.1093/hmg/ddaf091","DOIUrl":"https://doi.org/10.1093/hmg/ddaf091","url":null,"abstract":"Background: Parkinson 's disease (PD) is a common neurodegenerative disease. Aggregates formed by α-synuclein (α-Syn) are the main pathological changes of PD. In this study, the effects of Calcium homeostasis modulator 2 (Calhm2) on α-syn-induced neurotoxicity in PD were evaluated.Methods: Primary neurons were treated with α-Syn PFF to mimic the PD cellular model. Genes and proteins were evaluated utilizing RT-qPCR, Western blot and immunofluorescence, respectively. Cell damage was assessed using CCK-8 and LDH assay. Cellular oxidative stress was assessed via the detection of SOD, GSH and ROS level. Mitochondrial membrane potential, ATP level, AIF nuclear translocation and intracellular Ca2+ were determined for the assessment of Parthanatos. HE and immunofluorescence of TH and NeuN was detected pathological changes in vivo.Results: α-Syn PFF administration greatly resulted in oxidative stress, calcium overload and PARP-1 dependent Parthanatos in primary neurons. Following α-Syn PFF administration, Calhm2 and Calhm3, key calcium homeostasis modulator (Calhm) proteins, were markedly elevated in neurons, while Calhm1 expression exhibited a little change. In addition, suppression of Calhm2 obviously mitigated α-Syn PFF-induced oxidative stress injury, calcium overload and PARP-1 dependent Parthanatos in vitro. Similarly, in vivo results demonstrated that α-Syn PFF treatment led to PARP-1-dependent Parthanatos and nerve injury, while these effects were reversed by Calhm2 knockdown.Conclusion: Calhm2 repression lightened α-Syn aggregation-induced neurotoxicity and PARP-1-dependent Parthanatos in PD, providing a novel therapeutic target for PD treatment.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Expression of Concern: A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic Tau mouse model of Alzheimer disease. 关注的表达：在阿尔茨海默病的转基因Tau小鼠模型中，Drp1的部分减少改善了认知行为，增强了线粒体自噬、自噬和树突棘。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-11 DOI: 10.1093/hmg/ddaf099

引用次数: 0

Expression of Concern: Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer's disease. 关注表达：在阿尔茨海默病小鼠模型中，海马突变体APP和淀粉样蛋白β诱导的认知能力下降、树突状脊柱丢失、自噬缺陷、线粒体自噬和线粒体异常。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-11 DOI: 10.1093/hmg/ddaf097

引用次数: 0

Expression of Concern: Hippocampal phosphorylated tau induced cognitive decline, dendritic spine loss and mitochondrial abnormalities in a mouse model of Alzheimer's disease. 关注表达：海马磷酸化tau诱导阿尔茨海默病小鼠模型的认知能力下降、树突状脊柱丢失和线粒体异常。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-11 DOI: 10.1093/hmg/ddaf098

引用次数: 0

Second-hit CDH1 gene mechanisms in hereditary diffuse gastric and lobular breast cancer syndrome: frequency and impact on tumorigenesis. 二击CDH1基因在遗传性弥漫性胃癌和小叶性乳腺癌综合征中的作用机制：频率及其对肿瘤发生的影响

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-09 DOI: 10.1093/hmg/ddaf092

Giovanni Corso, Francesca Magnoni, Matteo Dal Molin, Elena Marino, Luca Nicosia, Filippo Pesapane, Douglas M Noonan, Adriana Albini

{"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":"https://doi.org/10.1093/hmg/ddaf092","url":null,"abstract":"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.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-09","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}

引用次数: 0

Mistargeting and ER retention of CLN7 patient-associated nonsense and sequence deletion mutations as a novel cause for CLN7 disease. CLN7患者相关无义和序列缺失突变的错靶和ER保留是CLN7疾病的新原因

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-09 DOI: 10.1093/hmg/ddaf089

Federica Valigi, Liana Uebler, Stephan Storch

{"title":"Mistargeting and ER retention of CLN7 patient-associated nonsense and sequence deletion mutations as a novel cause for CLN7 disease.","authors":"Federica Valigi, Liana Uebler, Stephan Storch","doi":"10.1093/hmg/ddaf089","DOIUrl":"https://doi.org/10.1093/hmg/ddaf089","url":null,"abstract":"CLN7 disease is a neurodegenerative lysosomal storage disorder caused by defects in MFSD8. We performed a comprehensive analysis of patient mutations causing CLN7 disease, variant late-infantile and non-syndromic adult phenotypes. Our analyses of protein expression and post-translational modifications, such as proteolytic cleavage and complex type N-linked oligosaccharide processing, along with double immunofluorescence analyses, demonstrated that the nonsense mutations p.Q206X, p.W456X, p.Q474X, and p.R482X, or the in-frame deletion mutation p.V109_I113del, resulted in decreased protein levels at steady state compared with wild type CLN7 and showed mistargeting and ER retention as the primary cause for loss of CLN7 function. We also investigated several missense mutations clustered in transmembrane domain 11 that affect conserved residues, which are believed to be important for CLN7 function. Analysis of protein levels, complex type N-glycosylation, proteolytic cleavage in lysosomes, and colocalization with lysosomal marker proteins in double immunofluorescence analyses showed that patient mutations p.T458L, p.R465Q, and p.R465W did not affect protein stability or correct lysosomal targeting of CLN7, indicating functional impairment. The missense mutation p.M454T resulted in increased cysteine protease-mediated turnover of mutant CLN7 in lysosomes. Using an assay to measure the generation of an enlarged endosome phenotype in cells overexpressing CLN7 carrying missense mutations, a loss of CLN7 function could not be detected. The effects of missense mutations in transmembrane domain 11 on CLN7 function remain to be investigated. In summary, our study revealed mistargeting and ER retention of nonsense and in-frame deletion mutations in MFSD8 as a cause of CLN7 disease, variant late-infantile phenotype.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Old vs. new local ancestry inference in HCHS/SOL: a comparative study. HCHS/SOL的新旧本地祖先推断：一项比较研究。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-09 DOI: 10.1093/hmg/ddaf093

Xueying Chen, Hao Wang, Iris Broce, Anders Dale, Bing Yu, Laura Y Zhou, Xihao Li, Maria Argos, Martha L Daviglus, Jianwen Cai, Nora Franceschini, Tamar Sofer

{"title":"Old vs. new local ancestry inference in HCHS/SOL: a comparative study.","authors":"Xueying Chen, Hao Wang, Iris Broce, Anders Dale, Bing Yu, Laura Y Zhou, Xihao Li, Maria Argos, Martha L Daviglus, Jianwen Cai, Nora Franceschini, Tamar Sofer","doi":"10.1093/hmg/ddaf093","DOIUrl":"10.1093/hmg/ddaf093","url":null,"abstract":"Hispanic/Latino populations are admixed, with genetic contributions from multiple ancestral populations. To uncover genetic associations in these populations, researchers often turn to admixture mapping, which relies on inferred counts of \"local\" ancestry, i.e. the source ancestral population at a locus. Local ancestries are inferred using external reference panels that represent ancestral populations, making the choice of inference method and reference panel critical. This study used a dataset of Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) to evaluate how updates in local ancestry inference (LAI) affect results, specifically, the 'old' LAI performed using a popular inference method RFMix alongside 'new' inferences performed using Fast Local Ancestry Estimation (FLARE) with an updated reference panel. We compared their performance in terms of global and local ancestry correlations, as well as admixture mapping-based associations. Overall, the old and new inferences produced highly similar global and local ancestry estimates, with FLARE-based results closely matching those from RFMix in admixture mapping analyses. However, in some genomic regions, the old and new local ancestries showed relatively lower correlations (Pearson R < 0.9). Most of these regions (86.42%) were mapped to either ENCODE blacklist regions or gene clusters, compared to 7.67% of randomly-matched regions with high correlations (Pearson R > 0.97). These findings show that old and new inferences largely agree and suggest that regions of lower agreement are mostly due to genomic sequence contexts that lead to less stable inference, rather than due to the LAI software or genotyping technology used.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Macrophages: sentinels, warriors, and healers. 巨噬细胞：哨兵、战士和治疗者。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-06 DOI: 10.1093/hmg/ddaf087

Eduardo D Bernier, Eric Bartnicki, Kamal M Khanna

{"title":"Macrophages: sentinels, warriors, and healers.","authors":"Eduardo D Bernier, Eric Bartnicki, Kamal M Khanna","doi":"10.1093/hmg/ddaf087","DOIUrl":"https://doi.org/10.1093/hmg/ddaf087","url":null,"abstract":"Macrophages are versatile innate immune cells that act as sentinels, warriors, and healers in virtually every tissue. This review synthesizes current insights into their developmental origins and the organ-specific cues that imprint diverse tissue-resident and monocyte-derived programs. We detail how pattern-recognition pathways, metabolic and epigenetic rewiring, and environmental signals govern macrophage plasticity, steering transitions between pro-inflammatory and reparative phenotypes during homeostasis, infection, and sterile injury. Dysregulated macrophage responses drive chronic inflammatory, autoimmune, metabolic, neurodegenerative, and neoplastic diseases; inter-individual variability rooted in genetic polymorphisms and enhancer landscapes further modulates susceptibility. Advances in single-cell and spatial multi-omics are redefining macrophage subsets and exposing disease-associated states, while approaches such as checkpoint blockade, chimeric antigen receptor macrophages, nanoparticles, metabolic modulators, and pro-resolving mediators showcase the therapeutic promise of re-programming these cells. Remaining challenges include integrating the layered genetic, metabolic, and microenvironmental inputs that dictate macrophage fate. Addressing these gaps will unlock precision strategies that harness macrophage plasticity to combat infection, resolve inflammation, repair tissue, and augment anti-tumor immunity.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

De novo missense variants of KCNA3, KCNA4, and KCNA6 cause early onset developmental epileptic encephalopathy. KCNA3、KCNA4和KCNA6的新生错义变异可引起早发性发育性癫痫性脑病。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-06-05 DOI: 10.1093/hmg/ddaf090

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

{"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":"https://doi.org/10.1093/hmg/ddaf090","url":null,"abstract":"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.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-05","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}

引用次数: 0