Human molecular genetics最新文献_第4页

Brain multi-omic Mendelian randomisation to identify novel drug targets for gliomagenesis. 通过脑多组学孟德尔随机法确定胶质瘤发生的新型药物靶点。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-11-20 DOI: 10.1093/hmg/ddae168

Zak A Thornton, Lily J Andrews, Huiling Zhao, Jie Zheng, Lavinia Paternoster, Jamie W Robinson, Kathreena M Kurian

{"title":"Brain multi-omic Mendelian randomisation to identify novel drug targets for gliomagenesis.","authors":"Zak A Thornton, Lily J Andrews, Huiling Zhao, Jie Zheng, Lavinia Paternoster, Jamie W Robinson, Kathreena M Kurian","doi":"10.1093/hmg/ddae168","DOIUrl":"https://doi.org/10.1093/hmg/ddae168","url":null,"abstract":"Background: Genetic variants associated with molecular traits that are also associated with liability to glioma can provide causal evidence for the identification and prioritisation of drug targets.Methods: We performed comprehensive two-sample Mendelian randomisation (Wald ratio and/or IVW) and colocalisation analyses of molecular traits on glioma. Instrumentable traits (QTLs P < 5 × 10-8) were identified amongst 11 985 gene expression measures, 13 285 splicing isoforms and 10 198 protein abundance measures, derived from 15 brain regions. Glioma summary-level data was extracted from a genome-wide association meta-analysis of 12 496 cases and 18 190 controls.Results: We found evidence for causal effect of 22 molecular traits (across 18 genes/proteins) on glioma risk. Thirteen molecular traits have been previously linked with glioma risk and five were novel; HBEGF (5q31.3) expression and all glioma [OR 1.36 (95%CI 1.19-1.55); P = 4.41 × 10-6]; a CEP192 (18p11.21) splice isoform and glioblastoma [OR 4.40 (95%CI 2.28-8.48); P = 9.78 × 10-4]; a FAIM (3q22.3) splice isoform and all glioma [OR 2.72-3.43; P = 1.03 × 10-5 to 1.09 × 10-5]; a SLC8A1 (2p22.1) splice isoform and all glioma [OR 0.37 (95%CI 0.24-0.56; P = 5.72 × 10-6]; D2HGDH (2q37.3) protein and all glioma [OR 0.86 (95%CI 0.80-0.92); P = 5.94 × 10-6)].Conclusions: We provide robust causal evidence for prioritising genes and their protein products in glioma research. Our results highlight the importance of alternative splicing as a mechanism in gliomagenesis and as an avenue for exploration of drug targets.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675657","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

ZBTB24 is a conserved multifaceted transcription factor at genes and centromeres that governs the DNA methylation state and expression of satellite repeats. ZBTB24 是基因和中心粒上的一种保守的多方面转录因子，可控制 DNA 甲基化状态和卫星重复序列的表达。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-11-20 DOI: 10.1093/hmg/ddae163

Giacomo Grillo, Ekaterina Boyarchuk, Seed Mihic, Ivana Ivkovic, Mathilde Bertrand, Alice Jouneau, Thomas Dahlet, Michael Dumas, Michael Weber, Guillaume Velasco, Claire Francastel

{"title":"ZBTB24 is a conserved multifaceted transcription factor at genes and centromeres that governs the DNA methylation state and expression of satellite repeats.","authors":"Giacomo Grillo, Ekaterina Boyarchuk, Seed Mihic, Ivana Ivkovic, Mathilde Bertrand, Alice Jouneau, Thomas Dahlet, Michael Dumas, Michael Weber, Guillaume Velasco, Claire Francastel","doi":"10.1093/hmg/ddae163","DOIUrl":"https://doi.org/10.1093/hmg/ddae163","url":null,"abstract":"Since its discovery as a causative gene of the Immunodeficiency with Centromeric instability and Facial anomalies syndrome, ZBTB24 has emerged as a key player in DNA methylation, immunity and development. By extensively analyzing ZBTB24 genomic functions in ICF-relevant mouse and human cellular models, we document here its multiple facets as a transcription factor, with key roles in immune response-related genes expression and also in early embryonic development. Using a constitutive Zbtb24 ICF-like mutant and an auxin-inducible degron system in mouse embryonic stem cells, we showed that ZBTB24 is recruited to centromeric satellite DNA where it is required to establish and maintain the correct DNA methylation patterns through the recruitment of DNMT3B. The ability of ZBTB24 to occupy centromeric satellite DNA is conserved in human cells. Together, our results unveiled an essential and underappreciated role for ZBTB24 at mouse and human centromeric satellite repeat arrays by controlling their DNA methylation and transcription status.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675676","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

Investigating MATN3 and ASPN as novel drivers of gastric cancer progression via EMT pathways. 研究 MATN3 和 ASPN 通过 EMT 通路作为胃癌进展的新型驱动因素。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-11-20 DOI: 10.1093/hmg/ddae129

Jing Li, Bo Xie, Hu Wang, QingKang Wang, YongYou Wu

{"title":"Investigating MATN3 and ASPN as novel drivers of gastric cancer progression via EMT pathways.","authors":"Jing Li, Bo Xie, Hu Wang, QingKang Wang, YongYou Wu","doi":"10.1093/hmg/ddae129","DOIUrl":"10.1093/hmg/ddae129","url":null,"abstract":"Gastric cancer (GC) is a leading cause of cancer-related deaths globally, necessitating the identification of novel therapeutic targets. This study investigates the roles of MATN3 and ASPN in GC progression via the epithelial-mesenchymal transition (EMT) pathway. Analysis of the Cancer Genome Atlas-Stomach Adenocarcinoma (TCGA-STAD) dataset revealed that both MATN3 and ASPN are significantly upregulated in GC tissues and correlate with poor patient survival. Protein-protein interaction and co-expression analyses confirmed a direct interaction between MATN3 and ASPN, suggesting their synergistic role in EMT activation. Functional assays demonstrated that MATN3 promotes GC cell proliferation, migration, and invasion, while its knockdown inhibits these malignant behaviors and induces apoptosis. ASPN overexpression further amplified these oncogenic effects. In vivo, studies in a mouse model corroborated that co-overexpression of MATN3 and ASPN enhances tumor growth and metastasis. These findings highlight the MATN3-ASPN axis as a potential therapeutic target in GC, offering new insights into the molecular mechanisms driving GC progression.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"2035-2050"},"PeriodicalIF":3.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142285998","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

The regulation of miRNAs using curcumin and other polyphenols during the prevention and treatment of Alzheimer's disease. 在预防和治疗阿尔茨海默病的过程中利用姜黄素和其他多酚调节 miRNA。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-11-19 DOI: 10.1093/hmg/ddae154

XiYun Wang, Sale Zhang, Ying Li, Yu Zhang

{"title":"The regulation of miRNAs using curcumin and other polyphenols during the prevention and treatment of Alzheimer's disease.","authors":"XiYun Wang, Sale Zhang, Ying Li, Yu Zhang","doi":"10.1093/hmg/ddae154","DOIUrl":"https://doi.org/10.1093/hmg/ddae154","url":null,"abstract":"Alzheimer's disease (AD), a prevalent neurodegenerative disorder, predominantly affects individuals over the age of 65 and poses significant challenges in terms of effective management and treatment. The disease's pathogenesis involves complex molecular pathways including misfolded proteins accumulation, neuroinflammation, and synaptic dysfunction. Recent insights have highlighted the role of microRNAs (miRNAs) as critical regulators within these pathways, where they influence gene expression and contribute to the pathophysiological landscape of AD. Notably, emerging research has demonstrated that polyphenols, including curcumin, might modulate miRNA activity, thus offering a novel approach to mitigate AD symptoms and progression. This review explores the potential mechanisms through which polyphenols regulate miRNA expression and activity, specifically focusing on autophagy enhancement and inflammation reduction in the context of AD. We provide a detailed examination of key studies linking miRNA dysregulation to AD pathogenesis and discuss how polyphenols might correct these aberrations. The findings presented here underscore the therapeutic potential of polyphenols in AD treatment via miRNA modulation, pointing to new directions in disease management strategies and highlighting the need for targeted research into miRNA-based interventions.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675672","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

Correction to: Expanded CAG/CTG repeats resist gene silencing mediated by targeted epigenome editing. 更正：扩展的 CAG/CTG 重复序列可抵制靶向表观基因组编辑介导的基因沉默。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-11-15 DOI: 10.1093/hmg/ddae167

引用次数: 0

Genetic analysis implicates ERAP1 and HLA as risk factors for severe Puumala virus infection. 遗传分析表明，ERAP1 和 HLA 是严重 Puumala 病毒感染的风险因素。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-11-13 DOI: 10.1093/hmg/ddae158

Hele Haapaniemi, Satu Strausz, Anniina Tervi, Samuel E Jones, Mari Kanerva, Erik Abner, Anne-Marie Fors Connolly, Hanna M Ollila

{"title":"Genetic analysis implicates ERAP1 and HLA as risk factors for severe Puumala virus infection.","authors":"Hele Haapaniemi, Satu Strausz, Anniina Tervi, Samuel E Jones, Mari Kanerva, Erik Abner, Anne-Marie Fors Connolly, Hanna M Ollila","doi":"10.1093/hmg/ddae158","DOIUrl":"https://doi.org/10.1093/hmg/ddae158","url":null,"abstract":"Puumala virus (PUUV) infections can cause severe illnesses such as Hemorrhagic Fever with Renal Syndrome in humans. However, human genetic risk factors contributing to disease severity are still poorly understood. Our goal was to elucidate genetic factors contributing to PUUV infections and understand the biological mechanisms underlying individual vulnerability to PUUV infections. Leveraging data from the FinnGen study, we conducted a genome-wide association study on severe Hemorrhagic Fever with Renal Syndrome caused by PUUV with 2227 cases. We identified associations at the Human Leukocyte Antigen (HLA) locus and ERAP1 with severe PUUV infection. HLA molecules are canonical mediators for immune recognition and response. ERAP1 facilitates immune system recognition and activation by cleaving viral proteins into smaller peptides which are presented to the immune system via HLA class I molecules. Notably, we identified that the lead variant (rs26653, OR = 0.84, P = 2.9 × 10-8) in the ERAP1 gene was a missense variant changing amino acid arginine to proline. From the HLA region, we showed independent and significant associations with both HLA class I and II genes. Furthermore, we showed independent associations with four HLA alleles with severe PUUV infection using conditional HLA fine mapping. The strongest association was found with the HLA-C*07:01 allele (OR = 1.54, P = 4.0 × 10-24) followed by signals at HLA-B*13:02, HLA-DRB1*01:01, and HLA-DRB1*11:01 alleles (P < 5 × 10-8). Our findings suggest an association of viral peptide processing with ERAP1 and antigen presentation through HLA alleles that may contribute to the development of severe PUUV disease.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619288","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

Analysis of genotype effects and inter-individual variability in iPSC-derived trisomy 21 neural progenitor cells. 分析 iPSC 衍生的 21 三体综合征神经祖细胞的基因型效应和个体间差异。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-11-13 DOI: 10.1093/hmg/ddae160

Sarah E Lee, Laura L Baxter, Monica I Duran, Samuel D Morris, Iman A Mosley, Kevin A Fuentes, Jeroen L A Pennings, Faycal Guedj, Diana W Bianchi

{"title":"Analysis of genotype effects and inter-individual variability in iPSC-derived trisomy 21 neural progenitor cells.","authors":"Sarah E Lee, Laura L Baxter, Monica I Duran, Samuel D Morris, Iman A Mosley, Kevin A Fuentes, Jeroen L A Pennings, Faycal Guedj, Diana W Bianchi","doi":"10.1093/hmg/ddae160","DOIUrl":"https://doi.org/10.1093/hmg/ddae160","url":null,"abstract":"Trisomy of human chromosome 21 (T21) gives rise to Down syndrome (DS), the most frequent live-born autosomal aneuploidy. T21 triggers genome-wide transcriptomic alterations that result in multiple atypical phenotypes with highly variable penetrance and expressivity in individuals with DS. Many of these phenotypes, including atypical neurodevelopment, emerge prenatally. To enable in vitro analyses of the cellular and molecular mechanisms leading to the neurological alterations associated with T21, we created and characterized a panel of genomically diverse T21 and euploid induced pluripotent stem cells (iPSCs). We subsequently differentiated these iPSCs to generate a panel of neural progenitor cells (NPCs). Alongside characterizing genotype effects from T21, we found that T21 NPCs showed inter-individual variability in growth rates, oxidative stress, senescence characteristics, and gene and protein expression. Pathway enrichment analyses of T21 NPCs identified vesicular transport, DNA repair, and cellular response to stress pathways. These results demonstrate T21-associated variability at the cellular level and suggest that cell lines from individuals with DS should not solely be analyzed as a homogenous population. Examining large cohorts of genetically diverse samples may more fully reveal the effects of aneuploidy on transcriptomic and phenotypic characteristics in T21 cell types. A panel of genomically diverse T21 and euploid induced pluripotent stem cells (iPSCs) were created and subsequently differentiated into neural progenitor cells (NPCs). T21 NPCs showed reduced growth, increased oxidative stress, and inter-individual variability in gene and protein expression. This inter-individual variability suggests that studies with large cohorts of genetically diverse T21 samples may more fully reveal the effects of aneuploidy.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619279","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

Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth syndrome. TAFAZZIN缺乏症的干细胞模型揭示了巴特综合征的新型组织特异性病理变化。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-11-13 DOI: 10.1093/hmg/ddae152

Olivia Sniezek Carney, Kodi W Harris, Yvonne Wohlfarter, Kyuna Lee, Grant Butschek, Arianna F Anzmann, Anne Hamacher-Brady, Markus A Keller, Hilary J Vernon

{"title":"Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth syndrome.","authors":"Olivia Sniezek Carney, Kodi W Harris, Yvonne Wohlfarter, Kyuna Lee, Grant Butschek, Arianna F Anzmann, Anne Hamacher-Brady, Markus A Keller, Hilary J Vernon","doi":"10.1093/hmg/ddae152","DOIUrl":"10.1093/hmg/ddae152","url":null,"abstract":"Barth syndrome (BTHS) is a rare mitochondrial disease caused by pathogenic variants in the gene TAFAZZIN, which leads to abnormal cardiolipin (CL) metabolism on the inner mitochondrial membrane. Although TAFAZZIN is ubiquitously expressed, BTHS involves a complex combination of tissue specific phenotypes including cardiomyopathy, neutropenia, skeletal myopathy, and growth delays, with a relatively minimal neurological burden. To understand both the developmental and functional effects of TAZ-deficiency in different tissues, we generated isogenic TAZ knockout (TAZ-KO) and WT cardiomyocytes (CMs) and neural progenitor cells (NPCs) from CRISPR-edited induced pluripotent stem cells (iPSCs). In TAZ-KO CMs we discovered evidence of dysregulated mitophagy including dysmorphic mitochondria and mitochondrial cristae, differential expression of key autophagy-associated genes, and an inability of TAZ-deficient CMs to properly initiate stress-induced mitophagy. In TAZ-deficient NPCs we identified novel phenotypes including a reduction in CIV abundance and CIV activity in the CIII2&CIV2 intermediate complex. Interestingly, while CL acyl chain manipulation was unable to alter mitophagy defects in TAZ-KO CMs, we found that linoleic acid or oleic acid supplementation was able to partially restore CIV abundance in TAZ-deficient NPCs. Taken together, our results have implications for understanding the tissue-specific pathology of BTHS and potential for tissue-specific therapeutic targeting. Moreover, our results highlight an emerging role for mitophagy in the cardiac pathophysiology of BTHS and reveal a potential neuron-specific bioenergetic phenotype.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619294","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

Developing and validating a comprehensive polygenic risk score to enhance keratoconus risk prediction. 开发并验证综合多基因风险评分，加强角膜病风险预测。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-11-13 DOI: 10.1093/hmg/ddae157

Weixiong He, Urmo Võsa, Teele Palumaa, Jue-Sheng Ong, Santiago Diaz Torres, Alex W Hewitt, David A Mackey, Puya Gharahkhani, Tõnu Esko, Stuart MacGregor

{"title":"Developing and validating a comprehensive polygenic risk score to enhance keratoconus risk prediction.","authors":"Weixiong He, Urmo Võsa, Teele Palumaa, Jue-Sheng Ong, Santiago Diaz Torres, Alex W Hewitt, David A Mackey, Puya Gharahkhani, Tõnu Esko, Stuart MacGregor","doi":"10.1093/hmg/ddae157","DOIUrl":"https://doi.org/10.1093/hmg/ddae157","url":null,"abstract":"Purpose: This study aimed to develop and validate a comprehensive polygenic risk score (PRS) for keratoconus, enhancing the predictive accuracy for identifying individuals at increased risk, which is crucial for preventing keratoconus-associated visual impairment such as post-Laser-assisted in situ keratomileusis (LASIK) ectasia.Methods: We applied a multi-trait analysis approach (MTAG) to genome-wide association study data on keratoconus and quantitative keratoconus-related traits and used this to construct PRS models for keratoconus risk using several PRS methodologies. We evaluated the predictive performance of the PRSs in two biobanks: Estonian Biobank (EstBB; 375 keratoconus cases and 17 902 controls) and UK Biobank (UKB: 34 keratoconus cases and 1000 controls). Scores were compared using the area under the curve (AUC) and odds ratios (ORs) for various PRS models.Results: The PRS models demonstrated significant predictive capabilities in EstBB, with the SBayesRC model achieving the highest OR of 2.28 per standard deviation increase in PRS, with a model containing age, sex and PRS showing good predictive accuracy (AUC = 0.72). In UKB, we found that adding the best-performing PRS to a model containing corneal measurements increased the AUC from 0.84 to 0.88 (P = 0.012 for difference), with an OR of 4.26 per standard deviation increase in the PRS. These models showed improved predictive capability compared to previous keratoconus PRS.Conclusion: The PRS models enhanced prediction of keratoconus risk, even with corneal measurements, showing potential for clinical use to identify individuals at high risk of keratoconus, and potentially help reduce the risk of post-LASIK ectasia.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619284","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

Ligand distances as key predictors of pathogenicity and function in NMDA receptors. 配体距离是预测 NMDA 受体致病性和功能的关键因素。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-11-13 DOI: 10.1093/hmg/ddae156

Ludovica Montanucci, Tobias Brünger, Nisha Bhattarai, Christian M Boßelmann, Sukhan Kim, James P Allen, Jing Zhang, Chiara Klöckner, Ilona Krey, Piero Fariselli, Patrick May, Johannes R Lemke, Scott J Myers, Hongjie Yuan, Stephen F Traynelis, Dennis Lal

{"title":"Ligand distances as key predictors of pathogenicity and function in NMDA receptors.","authors":"Ludovica Montanucci, Tobias Brünger, Nisha Bhattarai, Christian M Boßelmann, Sukhan Kim, James P Allen, Jing Zhang, Chiara Klöckner, Ilona Krey, Piero Fariselli, Patrick May, Johannes R Lemke, Scott J Myers, Hongjie Yuan, Stephen F Traynelis, Dennis Lal","doi":"10.1093/hmg/ddae156","DOIUrl":"https://doi.org/10.1093/hmg/ddae156","url":null,"abstract":"Genetic variants in the genes GRIN1, GRIN2A, GRIN2B, and GRIN2D, which encode subunits of the N-methyl-D-aspartate receptor (NMDAR), have been associated with severe and heterogeneous neurologic and neurodevelopmental disorders, including early onset epilepsy, developmental and epileptic encephalopathy, intellectual disability, and autism spectrum disorders. Missense variants in these genes can result in gain or loss of the NMDAR function, requiring opposite therapeutic treatments. Computational methods that predict pathogenicity and molecular functional effects of missense variants are therefore crucial for therapeutic applications. We assembled 223 missense variants from patients, 631 control variants from the general population, and 160 missense variants characterized by electrophysiological readouts that show whether they can enhance or reduce the function of the receptor. This includes new functional data from 33 variants reported here, for the first time. By mapping these variants onto the NMDAR protein structures, we found that pathogenic/benign variants and variants that increase/decrease the channel function were distributed unevenly on the protein structure, with spatial proximity to ligands bound to the agonist and antagonist binding sites being a key predictive feature for both variant pathogenicity and molecular functional consequences. Leveraging distances from ligands, we developed two machine-learning based predictors for NMDA variants: a pathogenicity predictor which outperforms currently available predictors and the first molecular function (increase/decrease) predictor. Our findings can have direct application to patient care by improving diagnostic yield for genetic neurodevelopmental disorders and by guiding personalized treatment informed by the knowledge of the molecular disease mechanism.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619290","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