Human molecular genetics最新文献

LRP8 inhibits bladder cancer cell ferroptosis by activating the Wnt/β-catenin-SCD1 positive feedback loop.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-24 DOI: 10.1093/hmg/ddaf024

Yong Zhao, Guohong Shi, Xiang Huang, Zhongyuan Zhang, Kaijun Liao, Hao Xiong, Zhiqiang Feng, Shihui Mao, Xu Zhang

{"title":"LRP8 inhibits bladder cancer cell ferroptosis by activating the Wnt/β-catenin-SCD1 positive feedback loop.","authors":"Yong Zhao, Guohong Shi, Xiang Huang, Zhongyuan Zhang, Kaijun Liao, Hao Xiong, Zhiqiang Feng, Shihui Mao, Xu Zhang","doi":"10.1093/hmg/ddaf024","DOIUrl":"https://doi.org/10.1093/hmg/ddaf024","url":null,"abstract":"Background: Advanced bladder cancer (bc) patients often have poor prognoses due to issues such as recurrence and drug resistance. The discovery of ferroptosis has opened new avenues for bc treatment; however, the specific regulatory mechanisms remain to be explored. This study aimed to investigate the mechanisms influencing ferroptosis in bc cells, with a particular focus on the role of low-density lipoprotein receptor-related protein 8 (LRP8).Methods: We utilized reverse transcription-quantitative polymerase chain reaction and western blot to assess the expression of LRP8 in bc cells, activation of the Wnt/β-catenin signaling pathway, and the expression of genes related to fatty acid synthesis. We measured changes in ferroptosis levels by evaluating mitochondrial membrane potential, Fe2+, malondialdehyde, and reactive oxygen species levels. A xenograft mouse model was employed to validate the impact of LRP8 on bc progression.Results: Cell experiments demonstrated a significant upregulation of LRP8 expression in bc cells. Knockdown of LRP8 induced ferroptosis in bc cells, a process directly triggered by the inhibition of the Wnt/β-catenin signaling pathway. Activation of the Wnt/β-catenin signaling pathway mediated by LRP8 upregulated the expression of stearoyl-CoA desaturase 1 (SCD1), subsequently leading to the suppression of ferroptosis. In vivo experiments indicated that LRP8 knockdown significantly impaired bc growth, accompanied by inhibition of the Wnt/β-catenin-SCD1 axis.Conclusion: LRP8 mediates the synthesis of monounsaturated fatty acids through the Wnt/β-catenin-SCD1 positive feedback loop, thereby inhibiting ferroptosis in bc cells. These findings provide a promising target for the regulation of ferroptosis in bc cells.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482044","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 impact of TRPV4 pathogenic mutations on barrier integrity.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-18 DOI: 10.1093/hmg/ddaf023

Gabriela Sampaio, Taylor Ismaili, Ali Torkamani, David G Breckenridge, Ashley Katana, David B Goldstein, Sunil Sahdeo

引用次数: 0

A TAF11 variant contributes to non-syndromic cleft lip only through modulating neural crest cell migration. TAF11变异仅通过调节神经嵴细胞迁移来促进非综合征性唇裂。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddae188

Dandan Li, Yu Tian, Barbara Vona, Xin Yu, Junyan Lin, Lan Ma, Shu Lou, Xiaofeng Li, Guirong Zhu, Yuting Wang, Mulong Du, Lin Wang, Yongchu Pan

{"title":"A TAF11 variant contributes to non-syndromic cleft lip only through modulating neural crest cell migration.","authors":"Dandan Li, Yu Tian, Barbara Vona, Xin Yu, Junyan Lin, Lan Ma, Shu Lou, Xiaofeng Li, Guirong Zhu, Yuting Wang, Mulong Du, Lin Wang, Yongchu Pan","doi":"10.1093/hmg/ddae188","DOIUrl":"10.1093/hmg/ddae188","url":null,"abstract":"The NC_000006.12: g.34887814C>G variant in TAF11 was identified as a potential functional variant in a Chinese pedigree including two non-syndromic cleft lip only (NSCLO) cases. Applying Chromatin Immunoprecipitation (ChIP), Electrophoretic mobility shift and super-shift assays, we found that the mutant G allele recruited more STAT1 and STAT3, and increased the expression of TAF11. RNA sequencing, GO and KEGG pathway enrichment, ChIP and dual-luciferase reporter assays revealed that TAF11 downregulated CDH1 and CTNND1 in the cell adhesion pathway by binding to their promoter regions and inhibiting transcriptional activities. Alcian blue staining, time-lapse photography, whole-mount in situ hybridization, phospho-Histone H3 immunofluorescence and TUNEL assays indicated that TAF11 and taf11 overexpression (TAF11OE and taf11OE, respectively) contributed to disturbed migration of cranial neural crest cells and abnormal craniofacial development, as well as increased death and deformity rates in zebrafish. In conclusion, a functionally relevant TAF11 variant, affecting cell migration via modulating CDH1 and CTNND1, was associated with etiology of NSCLO.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"392-401"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894074","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

Functional characterization of OXTR-associated enhancers.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddaf022

Dianne Laboy Cintrón, Rory R Sheng, Nadav Ahituv

引用次数: 0

Transcriptomic analysis of human cartilage identified potential therapeutic targets for hip osteoarthritis. 人软骨转录组学分析确定了髋关节骨关节炎的潜在治疗靶点。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddae200

Jingyi Huang, Ming Liu, Andrew Furey, Proton Rahman, Guangju Zhai

{"title":"Transcriptomic analysis of human cartilage identified potential therapeutic targets for hip osteoarthritis.","authors":"Jingyi Huang, Ming Liu, Andrew Furey, Proton Rahman, Guangju Zhai","doi":"10.1093/hmg/ddae200","DOIUrl":"10.1093/hmg/ddae200","url":null,"abstract":"Cartilage degradation is the hallmark of osteoarthritis (OA). The purpose of this study was to identify and validate differentially expressed genes (DEGs) in human articular cartilage that could serve as potential therapeutic targets for hip OA. We performed transcriptomic profiling in a discovery cohort (12 OA-free and 72 hip OA-affected cartilage) and identified 179 DEGs between OA-free and OA-affected cartilage after correcting for multiple testing (P < 2.97 × 10-6). Pathway and network analyses found eight hub genes to be associated with hip OA (ASPN, COL1A2, MXRA5, P3H1, PCOLCE, SDC1, SPARC, and TLR2), which were all confirmed using qPCR in a validation cohort (36 OA-free and 62 hip OA-affected cartilage) (P < 6.25 × 10-3). Our data showed that dysregulation of extracellular matrix formation and imbalance in the proportion of collagen chains may contribute to the development of hip OA, and SDC1 could be a promising potential therapeutic target. These findings provided a better understanding of the molecular mechanisms for hip OA and may assist in developing targeted treatment strategies.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"444-453"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948183","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}

引用次数: 0

Retraction of: Absence of ALOX5 gene prevents stress-induced memory deficits, synaptic dysfunction and tauopathy in a mouse model of Alzheimer's disease. 撤回：在阿尔茨海默病小鼠模型中，ALOX5 基因缺失可预防应激诱导的记忆缺陷、突触功能障碍和牛磺酸病变。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddae114

引用次数: 0

Q241R mutation of Braf causes neurological abnormalities in a mouse model of cardio-facio-cutaneous syndrome, independent of developmental malformations. Braf的Q241R突变导致心脏-面部-皮肤综合征小鼠模型的神经异常，独立于发育畸形。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddae196

Akira Moriya, Shin-Ichi Inoue, Fumihito Saitow, Moe Keitoku, Noato Suzuki, Etsumi Oike, Eriko Urano, Eiko Matsumoto, Hidenori Suzuki, Yoko Aoki, Hiroshi Ohnishi

{"title":"Q241R mutation of Braf causes neurological abnormalities in a mouse model of cardio-facio-cutaneous syndrome, independent of developmental malformations.","authors":"Akira Moriya, Shin-Ichi Inoue, Fumihito Saitow, Moe Keitoku, Noato Suzuki, Etsumi Oike, Eriko Urano, Eiko Matsumoto, Hidenori Suzuki, Yoko Aoki, Hiroshi Ohnishi","doi":"10.1093/hmg/ddae196","DOIUrl":"10.1093/hmg/ddae196","url":null,"abstract":"Constitutively active mutants of BRAF cause cardio-facio-cutaneous (CFC) syndrome, characterized by growth and developmental defects, cardiac malformations, facial features, cutaneous manifestations, and mental retardation. An animal model of human CFC syndrome, the systemic BrafQ241R/+ mutant mouse, has been reported to exhibit multiple CFC syndrome-like phenotypes. In this study, we analyzed the effects of Braf mutations on neural function, separately from their effects on developmental processes. To this end, we generated Braf mutant mice expressing BRAFQ241R specifically in mature excitatory neurons (n-BrafQ241R/+). We found no growth retardation or cardiac malformations in n-BrafQ241R/+ mice, indicating normal development. Behavioral analysis revealed that n-BrafQ241R/+ mice exhibited reduced home cage activity and learning disability, which were similar to those of systemic BrafQ241R/+ mice. The active form of ERK was increased in the hippocampus of n-BrafQ241R/+ mice, whereas basal synaptic transmission and synaptic plasticity in hippocampal Schaffer collateral-CA1 synapses seems to be normal. Transcriptome analysis of the hippocampal tissue revealed significant changes in the expression of genes involved in regulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway, synaptic function and memory formation. These data suggest that the neuronal dysfunction observed in the systemic CFC mouse model is due to the disruption of homeostasis of the RAS/MAPK signaling pathway by the activated Braf mutant after maturation, rather than abnormal development of the brain. A similar mechanism may be possible in human CFC syndrome.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"418-434"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948181","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 evaluation of targeted exome sequencing of candidate genes in a Han Chinese population with primary open-angle glaucoma. 中国汉族原发性开角型青光眼候选基因的靶向外显子组测序评价。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddae198

Yiwen Zhou, Youjia Zhang, Qingdan Xu, Xinghuai Sun, Yuhong Chen

{"title":"The evaluation of targeted exome sequencing of candidate genes in a Han Chinese population with primary open-angle glaucoma.","authors":"Yiwen Zhou, Youjia Zhang, Qingdan Xu, Xinghuai Sun, Yuhong Chen","doi":"10.1093/hmg/ddae198","DOIUrl":"10.1093/hmg/ddae198","url":null,"abstract":"Primary open-angle glaucoma (POAG), known as a common ocular disease with genetic heterogeneity, is characterized by progressive optic disc atrophy and visual field defects. This study aimed to assess the contribution of previously reported POAG-associated genes and investigate potential functional variations and genotype-phenotype correlations in a Han Chinese population. DNA from 500 cases and 500 controls was pooled and sequenced using a customized panel of 398 candidate genes. After prioritization, 21 SNPs from 16 genes were genotyped in the first replication cohort (500 cases and 500 controls), and 9 SNPs were genotyped in the second replication cohort (500 cases and 500 controls). Allelic associations and odds ratios were adjusted for age and sex, while linear regression assessed SNP correlations with POAG endophenotypes. Haplotype analysis and linkage disequilibrium were performed using Haploview. In silico prediction tools were used to predict pathogenicity and function. SNPs from MFN2, DGKG, PKHD1, PTPRJ, and LTBP2 were associated with POAG in at least one cohort, and SNPs from EXOC2, PTPRJ, and LTBP2 showed significant correlations with intraocular pressure. Additionally, haplotype analysis revealed a significant association between the EXOC2 TGC haplotype and POAG risk. We validated several candidate genes and identified novel SNPs, providing further insight into the genetic architecture of POAG in the Han Chinese population.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"435-443"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948182","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: Aqua-soluble DDQ reduces the levels of Drp1 and Aβ and inhibits abnormal interactions between Aβ and Drp1 and protects Alzheimer's disease neurons from Aβ- and Drp1-induced mitochondrial and synaptic toxicities. 关注的表达：水溶性DDQ降低Drp1和Aβ的水平，抑制Aβ和Drp1之间的异常相互作用，保护阿尔茨海默病神经元免受Aβ和Drp1诱导的线粒体和突触毒性。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-17 DOI: 10.1093/hmg/ddae204

引用次数: 0

5-aza-2-deoxycytidine improves skeletal muscle function in a mouse model for recessive RYR1-related congenital myopathy.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-02-13 DOI: 10.1093/hmg/ddaf021

Alexis Ruiz, Faiza Noreen, Hervé Meier, Katarzyna Buczak, Francesco Zorzato, Susan Treves

{"title":"5-aza-2-deoxycytidine improves skeletal muscle function in a mouse model for recessive RYR1-related congenital myopathy.","authors":"Alexis Ruiz, Faiza Noreen, Hervé Meier, Katarzyna Buczak, Francesco Zorzato, Susan Treves","doi":"10.1093/hmg/ddaf021","DOIUrl":"https://doi.org/10.1093/hmg/ddaf021","url":null,"abstract":"RYR1-related congenital myopathies are rare disorders that severely impair muscle function and the quality of life of patients and their families. To date no pharmacological therapies are available to treat the severe muscle weakness of affected patients. The most severe forms of RYR1-related congenital myopathies are caused by compound heterozygous mutations (nonsense/frameshift in one allele and a missense mutation in the other), leading to reduced RyR1 protein levels and altered biochemical composition of muscles. In this pre-clinical study, we treated a mouse model carrying the RyR1 p.Q1970fsX16 + p.A4329D compound heterozygous pathogenic variants (dHT mice) for 15 weeks with 0.05 mg/kg 5-aza-2'-deoxycytidine, an FDA-approved drug targeting DNA methyltransferases. We evaluated muscle strength, calcium homeostasis and muscle proteome and report that drug treatment improves all investigated parameters in dHT mice. Importantly, the beneficial effects were particularly significant in fast twitch muscles which are the first muscles to be impaired in patients. In conclusion, this study provides proof of concept for the pharmacological treatment of patients with recessive RYR1-related congenital myopathies with the FDA approved 5-aza-2'-deoxycytidine, supporting its use in a phase 1/2 clinical trial.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414173","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